Pyrazolopyrimidines as CRF antagonists

ABSTRACT

The present invention relates to pyrazolopyrimidines according to formula (I)  
                 
 
     and stereoisomers, isomers and salts thereof wherein R 1 -R 5  are selected from certain alkyl, aryl and heteroaryl species as defined in the specification wherein all of the compounds are useful as CRF antagonists and are thus useful in the treatment of neurological disorders as well as a multitude of other CRF associated diseases or conditions.

FIELD OF THE INVENTION

[0001] The present invention relates to novel compounds, compositions, and methods for the treatment of psychiatric disorders and neurological diseases, including major depression, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders, as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress. In particular, the present invention relates to novel pyrazolo[1,5-a]pyrimidines, pharmaceutical compositions containing such compounds and their use in treating psychiatric disorders, neurological diseases, immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress.

BACKGROUND OF THE INVENTION

[0002] Corticotropin releasing factor (herein referred to as CRF), a 41 amino acid peptide, is the primary physiological regulator of proopiomelanocortin (POMC)-derived peptide secretion from the anterior pituitary gland [J. Rivier et al., Proc. Nat. Acad. Sci. (USA) 80:4851 (1983); W. Vale et al., Science 213:1394 (1981)]. In addition to its endocrine role at the pituitary gland, immunohistochemical localization of CRF has demonstrated that the hormone has a broad extrahypothalamic distribution in the central nervous system and produces a wide spectrum of autonomic, electrophysiological and behavioral effects consistent with a neurotransmitter or neuromodulator role in brain [W. Vale et al., Rec. Prog. Horm. Res. 39:245 (1983); G. F. Koob, Persp. Behav. Med. 2:39 (1985); E.B. De Souza et al., J. Neurosci. 5:3189 (1985)]. There is also evidence that CRF plays a significant role in integrating the response of the immune system to physiological, psychological, and immunological stressors [J. E. Blalock, Physiological Reviews 69:1 (1989); J. E. Morley, Life Sci. 41:527 (1987)].

[0003] Clinical data provide evidence that CRF has a role in psychiatric disorders and neurological diseases including depression, anxiety-related disorders and feeding disorders. A role for CRF has also been postulated in the etiology and pathophysiology of Alzheimer's disease, Parkinson's disease, Huntington's disease, progressive supranuclear palsy and amyotrophic lateral sclerosis as they relate to the dysfunction of CRF neurons in the central nervous system [for review see E. B. De Souza, Hosp. Practice 23:59 (1988)].

[0004] In affective disorder, or major depression, the concentration of CRF is significantly increased in the cerebral spinal fluid (CSF) of drug-free individuals [C. B. Nemeroff et al., Science 226:1342 (1984); C. M. Banki et al., Am. J. Psychiatry 144:873 (1987); R. D. France et al., Biol. Psychiatry 28:86 (1988); M. Arato et al., Biol Psychiatry 25:355 (1989)]. Furthermore, the density of CRF receptors is significantly decreased in the frontal cortex of suicide victims, consistent with a hypersecretion of CRF [C. B. Nemeroff et al., Arch. Gen. Psychiatry 45:577 (1988)]. In addition, there is a blunted adrenocorticotropin (ACTH) response to CRF (i.v. administered) observed in depressed patients [P. W. Gold et al., Am J. Psychiatry 141:619 (1984); F. Holsboer et al., Psychoneuroendocrinology 9:147 (1984); P. W. Gold et al., New Eng. J. Med. 314:1129 (1986)]. Preclinical studies in rats and non-human primates provide additional support for the hypothesis that hypersecretion of CRF may be involved in the symptoms seen in human depression [R. M. Sapolsky, Arch. Gen. Psychiatry 46:1047 (1989)],. There is preliminary evidence that tricyclic antidepressants can alter CRF levels and thus modulate the numbers of CRF receptors in brain [Grigoriadis et al., Neuropsychopharmacology 2:53 (1989)].

[0005] It has also been postulated that CRF has a role in the etiology of anxiety-related disorders. CRF produces anxiogenic effects in animals and interactions between benzodiazepine/non-benzodiazepine anxiolytics and CRF have been demonstrated in a variety of behavioral anxiety models [D. R. Britton et al., Life Sci. 31:363 (1982); C. W. Berridge and A. J. Dunn Regul. Peptides 16:83 (1986)]. Preliminary studies using the putative CRF receptor antagonist a-helical ovine CRF (9-41) in a variety of behavioral paradigms demonstrate that the antagonist produces “anxiolytic-like” effects that are qualitatively similar to the benzodiazepines [C. W. Berridge and A. J. Dunn Horm. Behav. 21:393 (1987), Brain Research Reviews 15:71 (1990)].

[0006] Neurochemical, endocrine and receptor binding studies have all demonstrated interactions between CRF and benzodiazepine anxiolytics, providing further evidence for the involvement of CRF in these disorders. Chlordiazepoxide attenuates the “anxiogenic” effects of CRF in both the conflict test [K. T. Britton et al., Psychopharmacology 86:170 (1985); K. T. Britton et al., Psychopharmacology 94:306 (1988)] and in the acoustic startle test [N. R. Swerdlow et al., Psychopharmacology 88:147 (1986)] in rats. The benzodiazepine receptor antagonist (Rol15-1788), which was without behavioral activity alone in the operant conflict test, reversed the effects of CRF in a dose-dependent manner while the benzodiazepine inverse agonist (FG7142) enhanced the actions of CRF [K. T. Britton et al., Psychopharmacology 94:306 (1988)].

[0007] It has been further postulated that CRF has a role in immunological, cardiovascular or heart-related diseases such as hypertension, tachycardia and congestive heart failure, stroke, osteoporosis, premature birth, psychosocial dwarfism, stress-induced fever, ulcer, diarrhea, post-operative ileus and colonic hypersensitivity associated with psychopathological disturbance and stress.

[0008] The mechanisms and sites of action through which the standard anxiolytics and antidepressants produce their therapeutic effects remain to be elucidated. It has been hypothesized however, that they are involved in the suppression of the CRF hypersecretion that is observed in these disorders. Of particular interest is that preliminary studies examining the effects of a CRF receptor antagonist (a-helical CRF9-41) in a variety of behavioral paradigms have demonstrated that the CRF antagonist produces “anxiolytic-like” effects qualitatively similar to the benzodiazepines [for review see G. F. Koob and K. T. Britton, In: Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide, E. B. De Souza and C. B. Nemeroff eds., CRC Press p221 (1990)].

[0009] DuPont Merck PCT application U.S.94/11050 describes corticotropin releasing factor antagonist compounds of the formula:

[0010] and their use to treat psychiatric disorders and neurological diseases. Included in the description are fused pyridines and pyrimidines of the formula: where: V is CR^(1a) or N; Z is CR² or N; A is CR³ or N; and D is CR²⁸ or N.

[0011] WO 98/03510, published in January, 1998, also describes a series of CRF antagonist compounds having the formula:

[0012] wherein z is N or CR and A is N or CR.

[0013] WO 97/29109, published in August, 1997, similarly describes certain CRF antagonist compounds having the formula:

[0014] wherein Ar is phenyl, pyridyl and substituted versions thereof.

[0015] WO 98/08847, published Mar. 5, 1998, discloses CRF antagonist compounds of the formula:

[0016] wherein B is selected from a variety of non-aryl groups and R⁵ is selected from certain groups such as phenyl or pyridyl or substituted versions thereof.

[0017] WO 99/01454, published on Jan. 14, 1999, discloses CRF antagonist compounds of the formula:

[0018] wherein D is an aryl or heteroaryl group and R¹ is selected from certain non-aryl or non-heteroaryl groups. EP 0 269 859 (Ostuka, 1988) discloses pyrazolotriazine compounds of the formula

[0019] where R¹ is OH or alkanoyl, R² is H, OH, or SH, and R³ is an unsaturated heterocyclic group, naphthyl or substituted phenyl, and states that the compounds have xanthine oxidase inhibitory activity and are useful for treatment of gout.

[0020] EP 0 594 149 (Ostuka, 1994) discloses pyrazolotriazine and pyrazolopyrimidine compounds of the formula

[0021] where A is CH or N, R⁰ and R³ are H or alkyl, and R¹ and R² are H, alkyl, alkoxyl, alkylthio, nitro, etc., and states that the compounds inhibit androgen and are useful in treatment of benign prostatic hypertrophy and prostatic carcinoma.

[0022] U.S. Pat. No. 3,910,907 (ICI, 1975) discloses pyrazolotriazines of the formula:

[0023] where R¹ is CH₃, C₂H₅ or C₆H₅, X is H, C₆H₅, m-CH₃C₆H₄, CN, COOEt, Cl, I or Br, Y is H, C₆H₅, o-CH₃C₆H₄, or p-CH₃C₆H₄, and Z is OH, H, CH₃, C₂H₅, C₆H₅, n-C₃H₇, i-C₃H₇, SH, SCH₃, NHC₄H₉, or N(C₂H₅)₂, and states that the compounds are c-AMP phosphodiesterase inhibitors useful as bronchodilators.

[0024] U.S. Pat. No. 3,995,039 discloses pyrazolotriazines of the formula:

[0025] where R¹ is H or alkyl, R² is H or alkyl, R³ is H, alkyl, alkanoyl, carbamoyl, or lower alkylcarbamoyl, and R is pyridyl, pyrimidinyl, or pyrazinyl, and states that the compounds are useful as bronchodilators.

[0026] U.S. Pat. No. 5,137,887 discloses pyrazolotriazines of the formula

[0027] where R is lower alkoxy, and teaches that the compounds are xanthine oxidase inhibitors and are useful for treatment of gout.

[0028] U.S. Pat. No. 4,892,576 discloses pyrazolotriazines of the formula

[0029] where X is 0 or S, Ar is a phenyl, naphthyl, pyridyl or thienyl group, R₆-R₈ are H, alkyl, etc., and R_(g) is H, alkyl, phenyl, etc. The patent states that the compounds are useful as herbicides and plant growth regulants.

[0030] U.S. Pat. No. 5,484,760 and WO 92/10098 discloses herbicidal compositions containing, among other things, a herbicidal compound of the formula

[0031] where A can be N, B can be CR₃, R₃ can be phenyl or substituted phenyl, etc., R is -N(R₄)SO₂R₅ or -SO₂N(R₆)R₇ and R₁ and R₂ can be taken together to form where X, Y and Z are H, alkyl, acyl, etc. and D is 0 or

[0032] U.S. Pat. No. 3,910,907 and Senga et al., J. Med. Chem., 1982, 25, 243-249, disclose triazolotriazines cAMP phosphodiesterase inhibitors of the formula where Z is H, OH, CH₃, C₂H₅, C₆H₅, n-C₃H₇, iso-C₃H₇, SH, SCH₃, NH (n-C₄H₉) , or N (C₂H₅) ₂, R is H or CH₃, and R¹ is CH₃ or C₂H₅. The reference lists eight therapeutic areas where inhibitors of cAMP phosphodiesterase could have utility: asthma, diabetes mellitus, female fertility control, male infertility, psoriasis, thrombosis, anxiety, and hypertension.

[0033] WO95/35298 (Otsuka, 1995) discloses pyrazolopyrimidines and states that they are useful as analgesics. The compounds are represented by the formula

[0034] where Q is carbonyl or sulfonyl, n is 0 or 1, A is a single bond, alkylene or alkenylene, R¹ is H, alkyl, etc., R² is naphthyl, cycloalkyl, heteroaryl, substituted phenyl or phenoxy, R³ is H, alkyl or phenyl, R⁴ is H, alkyl, alkoxycarbonyl, phenylalkyl, optionally phenylthio-substituted phenyl, or halogen, R⁵ and R⁶ are H or alkyl.

[0035] EP 0 591 528 (Otsuka,1991) discloses anti-inflammatory use of pyrazolopyrimidines represented by the formula

[0036] where R₁, R₂, R₃ and R₄ are H, carboxyl, alkoxycarbonyl, optionally substituted alkyl, cycloalkyl, or phenyl, R₅ is SR₆ or NR₇R₈, R₆ is pyridyl or optionally substituted phenyl, and R₇ and R₈ are H or optionally substituted phenyl.

[0037] Springer et al, J. Med. Chem., 1976, vol. 19, no. 2, 291-296 and Springer U.S. Pat. Nos. 4021,556 and 3,920,652 disclose pyrazolopyrimidines of the formula

[0038] where R can be phenyl, substituted phenyl or pyridyl, and their use to treat gout, based on their ability to inhibit xanthine oxidase.

[0039] Joshi et al., J. Prakt. Chemie, 321, 2, 1979, 341-344, discloses compounds of the formula

[0040] where R¹ is CF₃, C₂F₅, or C₆H₄F, and R² is CH₃, C₂H₅, CF₃, or C₆H₄F.

[0041] Maquestiau et al., Bull. Soc. Belg., vol.101, no. 2, 1992, pages 131-136 discloses a pyrazolo[1,5-a]pyrimidine of the formula

[0042] Ibrahim et al., Arch. Pharm. (weinheim) 320, 487-491 (1987) discloses pyrazolo[1,5-a]pyrimidines of the formula

[0043] where R is NH2 or OH and Ar is 4-phenyl-3-cyano-2-aminopyrid-2-yl.

[0044] Other references which disclose azolopyrimidines inclued EP 0 511 528 (Otsuka, 1992), U.S. Pat. No. 4,997,940 (Dow, 1991), EP 0 374 448 (Nissan, 1990), U.S. Pat. No. 4,621,556 (ICN, 1997), EP 0 531 901 (Fujisawa, 1993), U.S. Pat. No. 4,567,263 (BASF, 1986), EP 0 662 477 (Isagro, 1995), DE 4 243 279 (Bayer, 1994), U.S. Pat. No. 5,397,774 (Upjohn, 1995), EP 0 521 622 (Upjohn, 1993), WO 94/109017 (Upjohn, 1994), J. Med. Chem., 24, 610-613 (1981), and J. Het. Chem., 22, 601 (1985) or others as additionally described herein.

SUMMARY OF THE INVENTION

[0045] In accordance with one aspect, the present invention provides novel compounds which bind to corticotropin releasing factor receptors, thereby altering the anxiogenic effects of CRF secretion. The compounds of the present invention are useful for the treatment of psychiatric disorders and neurological diseases, anxiety-related disorders, post-traumatic stress disorder, supranuclear palsy and feeding disorders as well as treatment of immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in mammals.

[0046] According to another aspect, the present invention provides novel compounds of formula (I) (described below) which are useful as antagonists of the corticotropin releasing factor. The compounds of the present invention exhibit activity as corticotropin releasing factor antagonists and appear to suppress CRF hypersecretion. The present invention also includes pharmaceutical compositions containing such compounds of formula (I), and methods of using such compounds for the suppression of CRF hypersecretion, and/or for the treatment of anxiogenic disorders.

[0047] According to yet another aspect, the present invention provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment of affective disorder, anxiety, depression, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal disease, anorexia nervosa or other feeding disorder, drug or alcohol withdrawal symptoms, drug addiction, inflammatory disorder, fertility problems, disorders, the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, or a disorder selected from inflammatory disorders such as rheumatoid arthritis and osteoarthritis, pain, asthma, psoriasis and allergies; generalized anxiety disorder; panic, phobias, obsessive-compulsive disorder; post-traumatic stress disorder; sleep disorders induced by stress; pain perception such as fibromyalgia; mood disorders such as depression, including major depression, single episode depression, recurrent depression, child abuse induced depression, and postpartum depression; dysthemia; bipolar disorders; cyclothymia; fatigue syndrome; stress-induced headache; cancer, human immunodeficiency virus (HIV) infections; neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease and Huntington's disease; gastrointestinal diseases such as ulcers, irritable bowel syndrome, Crohn's disease, spastic colon, diarrhea, and post operative ilius and colonic hypersensitivity associated by psychopathological disturbances or stress; eating disorders such as anorexia and bulimia nervosa; hemorrhagic stress; stress-induced psychotic episodes; euthyroid sick syndrome; syndrome of inappropriate antidiarrhetic hormone (ADH); obesity; infertility; head traumas; spinal cord trauma; ischemic neuronal damage (e.g., cerebral ischemia such as cerebral hippocampal ischemia); excitotoxic neuronal damage; epilepsy; cardiovascular and hear related disorders including hypertension, tachycardia and congestive heart failure; stroke; immune dysfunctions including stress induced immune dysfunctions (e.g., stress induced fevers, porcine stress syndrome, bovine shipping fever, equine paroxysmal fibrillation, and dysfunctions induced by confinement in chickens, sheering stress in sheep or human-animal interaction related stress in dogs); muscular spasms; urinary incontinence; senile dementia of the Alzheimer's type; multiinfarct dementia; amyotrophic lateral sclerosis; chemical dependencies and addictions (e.g., dependencies on alcohol, cocaine, heroin, benzodiazepines, or other drugs); drug and alcohol withdrawal symptoms; osteoporosis; psychosocial dwarfism and hypoglycemia in mammals. The preferred uses include treatment of depression and anxiety.

[0048] The present invention also relates to the use of a compound of formula I and other compounds generically and specifically disclosed herein in therapy.

[0049] According to a still further aspect of the invention, the compounds provided by this invention (and especially labelled compounds of this invention) are also useful as standards and reagents in determining the ability of a potential pharmaceutical to bind to the CRF receptor.

DETAILED DESCRIPTION OF INVENTION [1] Thus, in a first embodiment, the present invention provides a novel compound of formula I:

[0050]

[0051] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0052] R¹ is selected from the group consisting of

[0053] C₁₋₆alkyl,

[0054] C₂₋₁₀ alkenyl,

[0055] C₂₋₁₀ alkynyl,

[0056] C₃₋₆ cycloalkyl,

[0057] C₁₋₆ alkyloxy,

[0058] C₁₋₆ alkylS (O)_(n),

[0059] -NR^(1a)R^(1b) wherein r^(1a) and R^(1b) are independently selected from H, C₁₋₄ alkyl, -C(O)C₁₋₄alkyl,

[0060] -C(O)NR^(1a R) ^(1b) ,

[0061] —O—C (O) C₁₋₄alkyl,

[0062] -XR^(1c) wherein R^(1c) is selected from H or -C₁₋₄ alkylaryl;

[0063] X is selected from O or S(O),

[0064] wherein R¹ is substituted with 0-6 substituents selected from halogen, C₁₋₄ alkyl, C₁₋₆ alkyloxy, C₁₋₄ haloalkyl, -NR^(1a)R^(1b), -XR^(1c);

[0065] R is selected from the group consisting of

[0066] C₁ alkyl,

[0067] C₂₋₁₀ alkenyl,

[0068] C₂₋₁₀ alkynyl,

[0069] C₃-8 cycloalkyl,

[0070] C₃₋₆ cycloalkyl C₁₋₆ alkyl,

[0071] C₁₋₁₀ alkyloxy,

[0072] C₁₋₁₀ alkyloxyC₁₋₁₀ alkyl,

[0073] C₁₋₄ alkoxy C₁₋₄ alkyl,

[0074] -SO₂-C₁₋₁₀loalkyl

[0075] -SO₂R wherein R is aryl,

[0076] -SO₂R^(2b) wherein R is heteroaryl,

[0077] -NR^(2c)R^(2d)wherein R^(2c) and R^(2d) are independently selected from H, C₁₋₈ alkyl, S(O)_(n)C₁₋₄ alkyl, C(O)NR^(2c)R^(2d), CO₂C₁₋₄alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkyloxyc₁₋₆ alkyl, -C(O)C₁₋₄alkyl or R^(2c) and R^(2d) may join to form a heterocyclic ring having 0-3 heteroatoms selected from O, N or S,

[0078] halogen,

[0079] -CN,

[0080] -C(O)L wherein L is selected from NR^(2c)R^(2d), C₁₋₆ alkyl, H, -OC₁₋₆ alkyl, O(CH₂)_(m)OC₁₋₆alkyl, O(CH₂)_(m)NR^(2c)R^(2d), OH, aryl, heteroaryl or C(O)OC₁₋₆ alkyl, wherein m is 1-3, or more particularly from,

[0081] -C(O)NR^(2c)R^(2d),

[0082] -C(O)R wherein R is C₁₋₆ alkyl,

[0083] -C (O) O₁₋₄ alkyl,

[0084] -C(O) O (CH₂)₂OR wherein R is C₁₋₃ alkyl,

[0085] —C(O) O (CH₂)₂—NHR wherein R is C₁₋₃ alkyl,

[0086] —C (O) O (CH₂)₂—NR²,

[0087] -C(O)OH,

[0088] -C (O) H,

[0089] -C (O) Ph,

[0090] -C(O)R′ wherein R′ is aryl, heteroaryl or carboalkoxy;

[0091] n is 0, 1 or 2;

[0092] R is substituted with 0-3 substituents independently selected from R′, R″, R″′ wherein R′, R″ and R″′ are independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, hydroxyC₁₋₆ alkyl, C₁₋₆ alkyloxyC₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkyloxy, hydroxy, or

[0093] R is substituted with 0-3 substituents independently selected from:

[0094] halogen,

[0095] -CN,

[0096] -S (O)R ^(2e) wherein R^(2e) is selected from C₁₋₄alkyl, C₁₋₄

[0097] haloalkyl,C₁₋₄ alkyloxy C₁₋₄alkyl, C₃₋₆ cycloalkyl; -COR^(2f) wherein R^(2f) is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkyloxy C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkylC₁₋₄ alkyl;

[0098] -CO₂R^(2f),

[0099] -NR₂COR^(2f) wherein R^(2g) is selected from H, C₁₋₆ alkyl, C3-7 c-alkyl,

[0100] C₃₋₆ cycloalkyl C₁₋₆ alkyl;

[0101] -N(COR^(2f))₂

[0102] -NR^(2g)CONR^(2f)R^(2h), wherein R^(2h) is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy C₁₋₄ alkyl, C₃₋₆ cycloalkyl and C₃₋₆ cycloalkylC₁l₆ alkyl;

[0103] -NR^(2g)CO₂R^(2e),

[0104] -CONR^(2g)GR^(2h) ,

[0105] 1-morpholinyl,

[0106] 1-piperidinyl,

[0107] 1-piperazinyl,

[0108] and

[0109] C₃₋₈ cycloalkyl wherein 0-1 carbon atoms in the C48 cycloalkyl is replaced by a group selected from -O-, -S (O)-, -NR^(2g), -NCO₂R^(2e), -NCOR^(2e) , and -NSO₂R^(2e); and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from R^(2g)CO₂R^(2e), COR^(2e) and SO₂R^(2e)S; or

[0110] the group R^(2f), R^(2j), R^(2k), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -OR -NR^(2g)R^(2h), -C₁₋₆ alkylOR^(2g), and C₃₋₈ cycloalkyl which is substituted with 0-1 R²¹ and in wich 0-1 carbons of C₄.₈ cycloalkyl is replaced by -O -, wherein

[0111] R^(2i) is selected from aryl wherein aryl includes phenyl, naphthyl, indanyl and indenyl, each R^(2i) being substituted with 0-1 OR^(2m) and 0-5 substituents independently selected from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, nitro, -SH, -S(O)_(n)R^(2n), -COR^(2m) (O)R^(2n), N(COR^(2m))₂,

[0112] -NR^(2g)CONR^(2o)R^(2p), -NR^(2g)CO²R^(2n), -NR²OR^(2p) and -CONR^(2o)R^(2p);

[0113] R^(2j) is selected from heteroaryl wherein heteroaryl includes pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-s-oxide, 2,3-dihydro-benzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, nitro, OR^(2m), -SH, -S(O)_(n)R^(2h), -COR^(m), OC(O)R^(2h), -NR^(2g)COR^(2m), -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p), NR^(2g)CO₂R^(2h), -NR^(2o)R^(2p)- and -CONR^(2o)R^(2p) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(2g)CO₂R^(2e), COR^(2e) and SO₂R^(2e);

[0114] R^(2k) is heterocyclyl which is a saturated or partially saturated heteroaryl as defined for R^(2j) , each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, nitro, -OR , -SH, S(O)_(n)R^(2h), -COR^(2m), -OC(O)R^(2h), -NR^(2g)COR^(2m), -N(COR^(2m))₂ -NR^(2g)CONR^(2o)R^(2p), NR^(2g)COR^(2h), -NR^(2o)R^(2p) and -CONR^(2o)R^(2o) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(2f), CO₂R^(2e), COR²e and SO₂R^(2e);

[0115] wherein

[0116] R²¹ is H, C₁₋₄ alkyl, C₃₋₆ cycloalky-C₁₋₄ alkyl and C₃₋₈ cycloalkyl;

[0117] R^(2m) is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl, C₁₋₂ alkyloxy C₁₋₂ alkyl, C₁₋₄ haloalkyl, R^(2q)S (O)_(n)-C₁₋₄ alkyl and R^(2r) R^(2s)N-C₂₋₄ alkyl;

[0118] R^(2n) is H, C₁₋₆ alkyl, C₃₋₁₀ cyloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkyloxy C₁₋₂ alkyl, and C₁₋₄ haloalkyl;

[0119] R^(2o) and R²are independently selected at each occurrence from H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl and C014 haloalkyl;

[0120] R^(2q) is selected from C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl- C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl), heteroaryl and heleroaryl (C₁₋₄ alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy C₁₋₄ haloalkoxy, and dimethylamino;

[0121] R^(2r)R^(2s) taken together with the N form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl wherein N₄ in 1-piperiazinyl is substituted with 0-1 substituents selected from the group R^(2t), CO₂R^(2q), COR^(2q) and SO₂R^(2q);

[0122] R^(2t) is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy -C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl - C₁₋₆ alkyl, aryl, aryl (C₁₋₄ alkyl)-, heteroaryl and heteroaryl (C₁₋₄ alkyl);

[0123] R³ is selected from an aryl or heteroaryl group attached through an unsaturated carbon atom;

[0124] aryl is selected from phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkyloxy-C₁₋₄ alkyloxy, -OR^(2m) Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, -NO₂-SH, - S (O)_(n)R^(2n), -COR^(2m), -CO₂R^(2m), -OC(O)R^(2n), -NR^(2g)COR^(2m), -N(COR^(2m))₂ -NR^(2g)CONR^(2o)R^(2p), - NR^(2g)CO_(2h), -NR^(2o)R^(2p) and CONR^(2o)R^(2p) and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, -CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl;

[0125] heteroaryl is selected from the group pyridyl, pyrimidyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzo-furanyl, 2,3-dihydrobenzothienyl, 2,3-dihydro-benzothienyl-S-oxide, 2,3-dihydrobenzothienyl-s-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substitued at 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, F, I, C₁₋₄ haloalkyl, -CN, NRGR , nitro, -OR^(2m), -SH, -S(O)_(n)R^(2m) COR^(2m), -CO₂R^(2m), -OC(O)R^(2n), -NR^(2g)COR^(2m), -N(COR^(2m))₂ NR^(2g)CONR^(2o)R^(2p) and each heteroaryl being substituted at any nitrogen atom with 0-1 substituents selected from the group R^(2g), CO₂R^(3a), COR^(3a) and SO₂R^(3a) wherein,

[0126] R³a is selected from the group C₁,₆ alkyl, C₁₋₄ cycloalkyl-Cl6 alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

[0127] R⁴ and R⁵ are independently selected at each occurrence from H, Br, Cl, F, I, -CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋ ₈ cycloalkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, amino, C₁₋₄ alkylamino, (C₁₋₄ alkyl)₂ amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group consisting of C₁₋₇ alkyl, C₃₋₈ cycloalkyl, Br, Cl, F, I, -C(O)H, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkylamino and (C₁₋₄ alkyl)₂ amino and wherein R⁴ and R⁵ non-phenyl groups may be substituted with 0-5 substituents selected from OH, halogen, -C(O)H, -OC₁₋₆-alkyl and C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₇ c-alkyl, C₁₋₆ alkyl(OH)_(n)CO₂R wherein R is H or C₁₋₆ alkyl, C₁₋₆ alkyl(OH)_(n) wherein n is 0-3 or R⁴ and R⁵ may join together to form a C₃₋₆ alkylene chain; with the proviso that the compounds of Formula I with R¹, R², R³, R⁴ and R¹ as specifically defined below are excluded:

[0128] (a) a compound of formula I wherein R¹ is unsubstituted, unbranched (linear) C₁₋₃ alkyl and R2 is -C(O)-Ph (EP 0 129 847 A2, U.S. Pat. No. 4,521,422, U.S. Pat. No. 4,654,347);

[0129] (b) a compound of formula I, wherein R⁵ is H or C₁₋₃ alkyl and R³ is pyridyl, pyridyl-N-oxide, thien-3-yl or furan-3-yl or C₁₋₃ alkyl substituted versions thereof and R¹ is carboamoyl or unsubstituted, unbranched C ₁₋₃ alkyl, R² is F, Cl, Br, formyl, carboxyl, CN, hydroxymethyl, unsubstituted, unbranched C₁₋₃ alkyl, -C(O)R, -C(O)OR, -CH₂OR, -C(O)O(CH₂)₂OR, -C(O)O(CH₂)₂NHR, or -C(O)O(CH₂)₂NR² wherein R is C₁₋₃ alkyl (U.S. Pat. No. 4,281,000);

[0130] (c) a compound of formula I, wherein R¹ is unsubstituted, unbranched C₁₋₃ alkyl and R² is halogen, CN or -C(O)R wherein R is H, C₁₋₃ alkyl or C₁₋₄ alkoxy, R³ is Ph substituted with NR^(2g)C(O)R^(2m) (U.S. Pat. No. 4,626,538)

[0131] (d) a compound of formula I, R is CN, halogen, CO₂R with R equal to C₁₋₃ alkyl, unsubstituted, unbranched C₁₋₃ alkyl, C₁₋₃ haloalkyl or CONH₂ and R¹ is equal to OR, SR wherein R is C₁₋₃ alkyl, C₁₋₄ haloalkyl or C3-4 halocycloalkyl, and R³ is phenyl or substituted phenyl (U.S. Pat. No. 5,127,936);

[0132] (e) a compound of formula I, wherein R⁵ is H or C₁₋₃ alkyl; R³ is phenyl, ortho-trifluoromethylphenyl, meta-trifluorophenyl or meta-methoxyphenyl; R¹ is carbamoyl or unsubstituted C₁₋₃ alkyl; R² is halogen, formyl, carboxyl, cyano, hydroxymethyl, unsubstituted, unbranched C₁₋₃ alkyl, -C(O)R, -C(O)OR, CH₂OR, -C(O)O(CH₂)₂OR, C(O)O(CH₂)₂NHR or -C(O)O(CH₂)₂NR² wherein R is C₁₋₃ alkyl (U.S. Pat. No. 4,178,449);

[0133] (f) no entry

[0134] (g) in a compound of formula I, R² is CN, R¹ is methyl, R⁴ and R⁵ are H, R³ is phenyl substituted with imidazo (or 2-methylimidazo) through the imidazo nitrogen atom (Registry Reference 20, 21);

[0135] (h) in a compound of formula I, R² is CN, R¹ is SCH₃, R³ is para-chlorophenyl, R⁴ is SCH₃ and R⁵ is H (registry reference 25);

[0136] (i) in a compound of formula I, R² is CN, R¹ is SCH₃, R³ is pyrid-4-yl, R⁴ is SCH₃ and R⁵ is H (Registry Reference 26);

[0137] (j) in a compound of formula I, R² is CN, R¹ is SCH₃, R³ is Ph, R⁴ is SCH₃ and R⁵ is H (Registry Reference 27);

[0138] (k) in a compound of formula I, R² is C(O)NH₂, R is SCH₃, R³ is pyrid-3-yl, R⁴ is SCH₃ and R⁵ is H (Registry Reference 28);

[0139] (1) in a compound of formula I, R² is C(O)NH₂I R¹ is SCH₃, R³ is Ph, R⁴ is SCH₃ (or Ph) and R⁵ is H (Registry Reference 29, 31);

[0140] (m) in a compound of formula I, R² is C(O)OEt, R¹ is SCH₃, R³ is Ph, R⁴ is SCH₃ (or Ph) and R⁵ is H (registry reference 30, 32);

[0141] (n) in a compound of formula I, R¹ is N(C(O)CH₃)₂ R² is CH₂Ph(p-Me, p-Cl), R³ is Ph (p-ClPh), R⁴ is SCH₃ and R⁵ is H (Registry Reference 33, 34);

[0142] (o) in a compound of formula I, R¹ is N(C(O)CH₃)₂,R² is CH₂Ph(p-OMe), R³ is p-ClPh, R⁴ is SCH₃ and R⁵ is H (registry ref. 35);

[0143] (p) in a compound of formula I, R is CN, R² is CH₃, R³ is Ph, R⁴ is H and R⁵ is H (registry ref. 44);

[0144] (q) in a compound of formula I, R² is C(O)NH₂, R¹ is CH₃, R³ is Ph, R is CH₃ and R is H (reg. ref. 45);

[0145] (s) in a compound of formula I, R² is C(O)NH₂, R¹ is CH₃, R³ is pyrid-4-yl, R⁴ and R⁵ are H (reg. ref. 46);

[0146] (t) in a compound of formula I, R² is C(O)NH₂, R¹ is CH₃, R³ is m-CF₃Ph, R⁴ and R⁵ are H (reg. ref. 47);

[0147] (u) in a compound of formula I, R² is CN, R¹ is CH₃, R³ is Ph, R¹ is CH₃ and R⁵ is H (reg. ref. 48);

[0148] (v) in a compound of formula I, R is CN, R² is CH₃, R³ is pyrid-4-yl, R⁴ and R⁵ are H (reg. ref. 49);

[0149] (w) no entry

[0150] (x) in a compound of formula I, R is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is CH═CH—CH(OH)CH₂CH(OH)CH₂C(O)O-iPr (reg. ref. 75);

[0151] (y) in a compound of formula I, R² is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R¹ is CH═CH—CH(OH)CH₂CH(OH)CH₂C(O)O-nPr (reg. ref. 76);

[0152] (z) in a compound of formula I, R² is CH₃, R¹ is CH₃₁ R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is CH═CH—CH(OH)CH₂CH(OH)CH₂C(O)OMe (reg. ref. 77);

[0153] (aa) in a compound of formula I, R² is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is CH═CH—CH(OH)CH₂CH(OH)CH₂C(O)OH (reg. ref. 78);

[0154] (bb) in a compound of formula I, R² is CH₃ R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is -CH₂OH (reg. ref. 100);

[0155] (cc) in a compound of formula I, R² is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is -C(O)H (reg. ref. 105);

[0156] (dd) in a compound of formula I, R¹ is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is —CH═CH—C(O)H (reg. ref. 110);

[0157] (ee) in a compound of formula I, R² is CH₃, R¹ is CH , R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is CH═CH—CH(OH)CH₂CH(OH)CH₂C(O)OEt (reg. ref. 115);

[0158] (ff) in a compound of formula I, R² is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is CH═CH—CH(OH)CH₂CH(OH)CH₂C(O)ONa⁺(reg. ref. 120);

[0159] (gg) in a compound of formula I, R² is CN, R¹ is CF₃, R³ is m-Cl-Ph, R⁴ is CH₃ and R⁵ is H (reg. ref. 130); (hh) in a compound of formula I, R² is CN, R¹ is CF₃, R³ is m-CF₃-Ph, R⁴ is CH₃ and R⁵ is H (reg. ref. 132);

[0160] (ii) in a compound of formula I, R² is CN, R¹ is CF₃, R³ is Ph, R⁴ is CH₃ and R⁵ is H (reg. ref. 133);

[0161] (jj)-(mm) no entry

[0162] (nn) in a compound of formula I, R² is -C(O)NH₂, R¹ is Me, R³ is Ph, R⁴ is H and R⁵ is Me (reg. ref. 140);

[0163] (oo) in a compound of formula I, R² is CN, R¹ is Me, R³ is Ph, R⁴ is H and R⁵ is Me (reg. ref. 141);

[0164] (pp) in a compound of formula I, R² is CN, R¹ is Me, R³ is o-Cl,m-Cl-Ph, R⁴ is H and R⁵ is H (reg. ref. 144);

[0165] (qq) in a compound of formula I, R² is C(O)NH_(2,) R¹ is CH₃₁ R³ is Ph, R⁴ and R⁵ are H (reg. ref. 145);

[0166] (rr) in a compound of formula I, R² is C(O)NH_(2,) R¹ is CH₃₁ R³ is O-CL,m-Cl-Ph, R⁴ and R⁵ are H (reg. ref. 146);

[0167] (ss) in a compound of formula I, R² is C(O)OMe, R¹ is -SCH₂-Ph, R³ is Ph, R⁴is Me and R⁵ is H (reg. ref. 147);

[0168] (tt) in a compound of formula I, R² is C(O)OMe, R¹ is -SCH₂-Ph, R³ is Ph, R is H⁴ and R⁵ is H (reg. ref. 148);

[0169] (uu) in a compound of formula I, R² is C(O)Ph, R¹ is Me, R³ is pyrid-4-yl, R⁴ and R⁵ are H (reg. ref. 154);

[0170] (vv) in a compound of formula I, R² is C(O)Ph, R¹ is Me, R³ is m-CF₃ -Ph, R⁴ and R⁵ are H (reg. ref. 155);

[0171] (ww) in a compound of formula I, R² is C(O) Ph, R¹ is Me, R³ is pyrid-3-yl, R⁴ and R⁵ are H (reg. ref. 156);

[0172] (xx) in a compound of formula I, R² is CN, R¹ is SCH₃, R³ is Ph, R⁴ is Ph and R⁵ is H (reg. ref. 157);

[0173] (yy) in a compound of formula I, R² is CN, R¹ is SCH_(3,) R³ is Ph, R⁴ is Ph and R⁵ is H (reg. ref. 157);

[0174] (zz) in a compound of formula I, R² is Cl, R¹ is Et, R³ is pyrid-3-yl, R⁴ and R⁵ are H (reg. ref. 163);

[0175] (aaa) in a compound of formula I, R² is Co2H, R¹ is Et, R¹ is pyrid-3-yl, R⁴ and R⁵ are H (reg. ref. 164);

[0176] (bbb) in a compound of formula I, R² is CO₂H, R¹ is CH₃, R³ is pyrid-3-yl, R⁴ and R^(t) are H and H Cl salt (reg. ref. 165);

[0177] (ccc) in a compound of formula I, R² is C(O)OEt, R¹ is CH₃, R³ is pyrid-3-yl, R⁴ and R⁵ are H (reg. ref. 166);

[0178] (ddd) in a compound of formula I, R² is CN, R¹ is CH₃, R³ is pyrid-3-yl, R⁴ is H and R⁵ is CH₃ (reg. ref. 167);

[0179] (eee) in a compound of formula I, R² is CN, R¹ is CH₃, R³ is pyrid-3-yl, R⁴ and R⁵ are H (reg. ref. 168);

[0180] (fff) in a compound of formula I, R² is C(O)OEt, R¹ is Et, R³ is pyrid-3-yl, R⁴ and R⁵ are H (reg. ref. 169);

[0181] (ggg) in a compound of formula I, R² is ON, R¹ is Et, R³ is pyrid-3-yl, R⁴ and R⁵ are H (reg. ref. 170);

[0182] (hhh) in a compound of formula I, R² is CN, R¹ is CH₃, R³ is m-CF₃Ph, R⁴ and R⁵ are H (reg. ref. 172);

[0183] (iii) in a compound of formula I, R² is CN, R¹ is CH₂CN, R³ is m-CF₃-Ph, R⁴ and R⁵ are H (reg. ref . 173);

[0184] (jjj) in a compound of formula I, R² is C (O)OMe, R¹ is Me, R³ is m-CF₃-Ph, R⁴ and R⁵ are H (reg. ref. 174);

[0185] (kkk) in a compound of formula I, R² is CN, R¹ is Et, R¹ is m-OMe-Ph, R⁴and R⁵ are H (reg. ref. 175);

[0186] (lll) in a compound of formula I, R² is O(O)OEt, R¹ is Et, R³ is Ph, R⁴ and R¹ are H (reg. ref. 17 6);

[0187] (mmm) in a compound of formula I, R² is O(O)OEt, R¹ is Et, R³ is m-CF₃Ph, R⁴ and R⁵ are H (reg. ref. 177);

[0188] (nnn) in a compound of formula I, R² is CN, R¹ is Et, R³is m-CF₃Ph, R⁴ is H and R⁵ is CH₃ (reg. ref. 178);

[0189] (ooo) in a compound of formula I, R² is CN, R¹ is Et, R³ is

[0190] (ppp) in a compound of formula I, R² is CN, R¹ is O (O)NH_(2,) R³ is m-CF₃-Ph, R⁴ and R⁵ are H (reg. ref. 180);

[0191] (qqq) in a compound of formula I, R² is CN, R¹ is Et, R³ is Ph, R⁴ and R⁵ are H (reg. ref. 181).

[0192] [1′] In a preferred embodiment, the present invention provides a novel compound of formula I:

[0193] or a stereoisomer or pharmaceutically acceptable salt thereof, wherein:

[0194] R¹ is selected from the group consisting of

[0195] C₁₋₆ alkyl,

[0196] C₂₋₁₀ alkenyl,

[0197] C₂₋₁₀ alkynyl,

[0198] C₃₋₆ cycloalkyl,

[0199] C₁₋₆ alkyloxy,

[0200] C₁₋₆ alkylS(O)O,

[0201] -NR¹ R^(1b) wherein R^(1a) and R^(1b) are independently selected from H, C₁₋₄ alkyl, -C(O)C₁₋₄alkyl,

[0202] -C(O)NR^(1a)R^(1b),

[0203] -O-C (O) C₁₋₄alkyl,

[0204] -XR^(1c) wherein R^(1c) is selected from H or -C₁₋₄ alkylaryl; X is selected from O or S(O)_(n),

[0205] wherein R¹ is substituted with 0-6 substituents selected from halogen, C₁₋₄ alkyl, C₁₋₆ alkyloxy, C₁₋₄ haloalkyl, -NR^(1a)R^(1b), -XR^(1c);

[0206] R² is selected from the group consisting of

[0207] C₁₋₁₀ alkyl excluding unsubstituted, unbranched C₁₋₃alkyl,

[0208] C₂₋₁₀ alkenyl,

[0209] C₂₋₁₀ alkynyl,

[0210] C₃₋₈ cycloalkyl,

[0211] C₃₋₆ cycloalkyl C₁₋₆ alkyl,

[0212] C₁₋₁₀ alkyloxy,

[0213] C₁₋₁₀ alkyloxyC₁₋₁₀ alkyl,

[0214] C₁₋₄ alkoxy C₁₋₄ alkyl,

[0215] -SO₂-C₁₋₁₀ alkyl

[0216] -SO2R^(2a) wherein R^(2a) is aryl,

[0217] -SO₂R^(2b) wherein R^(2b) is heteroaryl,

[0218] -NR²cR²D wherein R²c and R²d are independently selected from H, C₁₋₈ alkyl, S(O).C₁₋₄ alkyl, C(O)NR R , C₂C₁,₄alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkyloxyC₁₋₆ alkyl, -C(O)C₁₋₄alkyl or R^(2c) and R^(2c) may join to form a heterocyclic ring having 0-3 heteroatoms selected from O, N or S,

[0219] n is 0, 1 or 2;

[0220] R² is substituted with 0-3 substituents independently selected from R′, R″, R″′ wherein R′, R″ and R″′ are independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, hydroxyC₁₋₆ alkyl, C₁₋₆ alkyloxyC₁₋₆ alkyl, C₂₋₆ alkenyl, C₁-6 alkyloxy, hydroxy, or

[0221] R² is substituted with 0-3 substituents independently selected from:

[0222] -CN,

[0223] -S(O)_(n)R^(2e) wherein R^(2e) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl,C₁₋₄ alkyloxy C₁₋₄alkyl, C₃₋₆ cycloalkyl;

[0224] -COR^(2f) wherein R^(2f) is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₄ alkyloxy C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkylc₁₋₄ alkyl;

[0225] -CO₂R^(2f),

[0226] -NR^(2g)COR^(2f) wherein R^(2g) is selected from H, C₁₋₆ alkyl, C₃₋₇c-alkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl;

[0227] -N(COR )₂,

[0228] -NR^(2g)CONR^(2f)R^(2h), wherein R^(2h) is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy C₁₋₄ alkyl, C₃₋₆ cycloalkyl and C₃₋₆ cycloalkylC₁₋₆ alkyl;

[0229] -NR^(2g)CO₂R^(2h),

[0230] -CONR^(2g)R^(2h),

[0231] 1-morpholinyl,

[0232] 1-piperidinyl,

[0233] 1-piperazinyl,

[0234] and

[0235] C₃₋₈ cycloalkyl wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from -O-, -S(O)_(n)-, N NCO₂R^(2e) , NCOR^(2e), and -NSO₂R^(2 e); and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from R^(2g), CO₂R^(2e), COR^(2e) and SO₂R^(2e) or

[0236] the group R^(2j), R^(2k), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -OR^(2g), -NR^(2g)R^(2h), -C₁₋₆ alkylOR^(2g), and C₃₋₈ cycloalkyl which is substituted with 0-1 R^(2l) and in wich 0-1 carbons of C₄₋₈ cycloalkyl is replaced by -O-, wherein R^(2j) is selected from heteroaryl wherein heteroaryl includes pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-s-oxide, 2,3-dihydro-benzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, nitro, OR^(2m), -SH, -S(O)_(n)R^(2h), -COR^(2m), -OC(O)R^(2h), -NR^(2g)COR^(2m), -N(COR^(2m))₂, -NR CONR^(2o)R^(2p), -NR^(2g)CO₂R^(2h), -NR^(2o)R^(2p) and -CONR^(2o)R^(2p) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(2g), CO₂R^(2e), COR^(2e) and SO₂R^(2e);

[0237] R^(2k) is heterocyclyl which is a saturated or partially saturated heteroaryl as defined for R^(2j), each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, nitro, -OR^(2m), -SH -S(O)_(n)R^(2h), -COR^(2m), -OC(O)R^(2h), -NR^(2g)COR^(2m), -N(COR^(2m)) -NR^(2g)CONR²⁰R^(2p), NR^(2g)CO₂R^(3h), -NR^(2o)R^(2p) and -CONR^(2o)R^(2p) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(2f), CO₂R_(2e), COR^(2e) and SO₂R^(2e);

[0238] wherein

[0239] R^(2l) is H, C₁₋₄ alkyl, C₃₋₆ cycloalky-C₁₋₄ alkyl and C₃₋₈ cycloalkyl; R^(2m) is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl, C₁₂ alkyloxy C₁₋₂ alkyl, C₁₋₄ haloalkyl, R^(2q)S (O)_(n)C₁₋₄ alkyl and R^(2r)R^(2s)N-C₂₋₄ alkyl;

[0240] R^(2n) is H, C₁₋₆ alkyl, C₃₋₁₀ cyloalkyl, C₃₋₆cycloalkyl-C₁₋₆ C_(1≢)alkyl, C₁₋₂ alkyloxy C₁₋₂ alkyl, and C₁₋₄ haloalkyl;

[0241] R^(2o) and R^(2p) are independently selected at each occurrence from H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl and C₁₋₄ haloalkyl;

[0242] R^(2q) is selected from C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-cC₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl- C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl), heteroaryl and heleroaryl (C₁₋₄ alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy C₁₋₄ haloalkoxy, and dimethylamino;

[0243] R^(2r)R^(2s) taken together with the N form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl wherein N₄ in 1-piperiazinyl is substituted with 0-1 substituents selected from the group R^(2t), CO₂R^(2q), COR^(2q) and SO₂R^(2q),

[0244] R^(2t) is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy -C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl -C₁₋₆ alkyl, aryl, aryl (C₁₋₄ alkyl)-, heteroaryl and heteroaryl (C₁₋₄ alkyl);

[0245] R³ is selected from an aryl or heteroaryl group attached through an unsaturated carbon atom;

[0246] aryl is selected from phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkyloxy-C₁₋₄ alkyloxy, -OR^(2m), Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, -NO₂, -SH, -S (O)_(n)R^(2n), -COR^(2m), -CO₂R^(2m), -OC(O)R^(2n), -NR^(2g)COR^(2m), -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p), -NR^(2g)CO₂R^(2h), -NR^(2o)R^(2p) and CONR^(2o)R^(2p) and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, -CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl;

[0247] heteroaryl is selected from the group pyridyl, pyrimidyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzo-furanyl, 2,3-dihydrobenzothienyl, 2,3-dihydro-benzothienyl-S-oxide, 2,3-dihydrobenzothienyl-s-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substitued at 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, F, I, C₁₋₄ haloalkyl, -CN, NR^(2g)R^(2h), nitro, -OR^(2m), -SH, -S(O)_(n)R^(2n), COR^(2m), -CO₂R^(2m), -OC(O)R^(2n), -NR^(2g)COR^(2m) , -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p) and each heteroaryl being substituted at any nitrogen atom with 0-1 substituents selected from the group, R^(2g), CO₂R^(3a), COR^(3a) and SO₂R^(3a) wherein,

[0248] R^(3a) is selected from the group C₁₋₆ alkyl, C₁₋₄ cycloalkyl-C ₁₋₆ alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, Calkoxy, C₁₋₄ haloalkoxy, and dimethylamino;

[0249] R⁴ and R⁵ are independently selected at each occurrence from H, Br, Cl, F, I, -CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, amino, C₁₋₄ alkylamino, (C₁₋₄ alkyl)₂ amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group consisting of C₁₋₇, alkyl, C₃₋₈ cycloalkyl, Br, Cl, F, I, -C(O)H, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkylamino and (C₁₋₄ alkyl)₂ amino and wherein R⁴ and R⁵ non-phenyl groups may be substituted with 0-5 substituents selected from OH, halogen, -C(O)H, -OC₁₋₆-alkyl and C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃ ₇ c-alkyl, C₁₋₆ alkyl(OH) CO₂R wherein R is H or C₁₋₆ alkyl, C₁₋₆ alkyl(OH). ,wherein n is 0-3 or R⁴ and R⁵ may join together to form a C₃₋₆ alkylene chain.

[0250] [2] The present invention relates to a compound as described directly above in [1] or [1] wherein

[0251] R¹ is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, -XR^(1c) wherein R¹ is substituted with 0-6 substituents selected from halogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl;

[0252] R² is selected from substituted-C.i₀ alkyl, branched C₃₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl,-NR^(2c)R^(2d) wherein, in the case of substituted-C₁₋₁₀ alkyl, 1-3 substitutents are independently selected from the group R^(2i), R^(2j), R^(2k), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -OR , -NR^(2g)gR^(2h), -C₁₋₆ alkylOR^(2g), and C₃₋₈ cycloalkyl which is substituted with 0-1 R^(2l) and in wich 0-1 carbons of C₄₋₈ cycloalkyl is replaced by -O- and wherein the R² groups, other than substituted-C₁₋₁₀ alkyl, are substituted with 0-3 substituents independently selected from the group R^(2i), R^(2j), R^(2k), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -OR^(2g), -NR^(2g)R^(2h), -C₁₋₆ alkylOR^(2g), and C₃₋₈ cycloalkyl which is substituted with 0-1 R^(2l) and in wich 0-1 carbons of C₄₋₈ cycloalkyl is replacedby -O-.

[0253] [3] The present invention also relates to a compound described in groups [1], [1′] or [2] wherein R³ is selected from an aryl group selected from phenyl or substituted versions thereof or a heteroaryl group selected from pyridyl or substituted versions thereof.

[0254] [4] The present invention relates to a compound described directly above in groups [1′] and [1]-[3] wherein R³ is substituted with 0-4 substituents independently selected from halogen, C₁₋₄ alkyloxy, C₁,₆ alkyl or NR′R″ wherein R′ and R″ are independently selected from H or C₁₋₆ alkyl.

[0255] [5] The present invention preferrably relates to a compound as described directly above in groups [1′] and [1]-[4] wherein R³ is selected from 2,4-dichlorophenyl, 2-chloro-4-methoxyphenyl, 2,4,6-trimethylphenyl, 2,4,6-trimethoxyphenyl, 2-dimethylamino-4-methyl-pyridin-5-yl, 2,4-dichloro-5-fluorophenyl, 2-chloro-4-methoxy-5-fluorophenyl, 2-chloro-4,5-dimethoxyphenyl or 2-chloro-4,5-dimethoxyphenyl.

[0256] [6] The present invention also preferrably relates to a compound as described in groups [1′] and [2]-[5] wherein R² is selected from C₁ alkyl of the formula -CR′R″R″′ wherein R′, R″ and R″′ are independently selected from H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, hydroxyC₁₋₆ alkyl, C₁₋₆ alkyloxyC₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkyloxy, hydroxy, with the proviso that each of R′, R″ and R″′ cannot be H;

[0257] or R² is selected from NR^(2c)CR^(2d) wherein R^(2c) and R^(2d) are independently selected from H or C₁₋₆ alkyl.

[0258] [7] The present invention preferrably relates to a compound according to groups [1′] and [1]-[6] wherein R³ is selected from an aryl or heteroaryl group attached through an unsaturated carbon atom wherein, aryl is phenyl, each phenyl being substituted with 0-5 substituents independently selected at each occurrence from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkyloxy-C₁₋₄ alkyloxy, -OR^(2m), Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, -NO₂, -SH, -S(O)_(n)R^(2n), -COR^(2m), -CO₂R^(2m), -OC(O)R^(2n), -NR^(2g)COR^(2m), -N(COR^(2m) )₂, -NR^(2g)CONR^(2o)R^(2p), -NR^(2g)CO₂R^(2h), -NR^(2o)R^(2p) and CONR^(2o)R^(2p) and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, -CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl and wherein, heteroaryl is selected at each occurrence from pyridyl, each pyridyl being substitued at 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, F, I, C₁₋₄ haloalkyl, -CN, nitro, -OR^(2m), -SH, -S(O)_(n)R^(2n), COR^(2m), CO₂R^(2m), -OC(O)R^(2n), -NR^(2g)COR^(2m), -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p) and each pyridyl being substituted at any nitrogen atom with 0-1 substituents selected from the group R^(2g), CO₂R^(3a), and SO₂R^(3a).

[0259] [8] The present invention preferrably relates to a compound of formula (I)

[0260] or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein

[0261] R¹ is selected from C₁₋₆ alkyl, C₁₋₆ alkyloxy, -SH or OH;

[0262] R² is selected from C₁₋₄ alkyl which is unsubstituted or substituted with 1-4 substitutents selected from C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkylOR^(2g), C₂₋₆ alkenyl or OR^(2g) wherein R²⁹ is H or C₁₋₆ alkyl;

[0263] R³ is selected from an aryl or heteroaryl group bonded through an unsaturated carbon atom that is unsubstituted or substituted with 1-4 substituents selected from Cl, F, I, Br, -OH, CF₃, S(O)_(n)C₁₋₆ alkyl, -OC₁₋₆ alkyl, C₁₋₆ alkyl or NR^(2g)R^(2h) wherein R^(2g) and R^(2h) are independently selected from H or C₁₋₆ alkyl;

[0264] R⁴ and R⁵ are independently selected from H, C₁₋₆ alkyl or C₁₋₆ alkyloxy,

[0265] with the proviso that when R¹ and R² are unsubstituted, unbranched C₁₋₃ alkyl, R³ may not be

[0266] wherein R′ is H or C₁₋₃ alkyl and R″ is H or o-trifluoromethyl, m-trifluoromethyl or m-methoxy (see U.S. Pat. No. 4,281,000).

[0267] [9] The present invention also relates to a compound according to group [8] wherein R³ is substituted with 2-4 substituents.

[0268] [10] The present invention also relates to a compound according to group [8] or[9] wherein R² is substituted with 1-4 substituents.

[0269] [11] The present invention also relates to a compound according to groups [8]-[10] having the formulae shown in Table 1.

[0270] [12] The present invention also relates to a method of antagonizing a CRF-1 receptor in mammals including humans wherein binding to the receptor causes and ultimately results in the treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of Formula (I) wherein

[0271] R¹ is selected from the group consisting of

[0272] C₁₋₆ alkyl,

[0273] C₂₋₁₀ alkenyl,

[0274] C₂₋₁₀ alkynyl,

[0275] C₃₋₆ cycloalkyl,

[0276] C₁₋₆ alkyloxy,

[0277] C₁₋₆ alkyls (O)_(n),

[0278] -NR^(1a)R^(1b) wherein R^(1a) and R^(1b) are independently selected from H, C₁₋₄ alkyl, -C(O)C₁₋₄alkyl,

[0279] -C(O)NR^(1a)R^(1b),

[0280] -O-C (O) C₁₋₄alkyl,

[0281] -XR^(1c) wherein R^(1c) is selected from H or -C₁₋₄ alkylaryl; X is selected from 0 or S(O)_(n),

[0282] wherein R¹ is substituted with 0-6 substituents selected from halogen, C₁₋₄ alkyl, C₁₋₆ alkyloxy, C₁₋₄ haloalkyl, -NR^(1a)R^(1b), XR^(1c);

[0283] R² is selected from the group consisting of

[0284] C₁₋₁₀ alkyl,

[0285] C₂₋₁₀ alkenyl,

[0286] C₂₋₁₀ alkynyl,

[0287] C₃₋₈ cycloalkyl,

[0288] C₃₋₆ cycloalkyl C₁₋₆ alkyl,

[0289] C₁₋₁₀ alkyloxy,

[0290] C₁₋₁₀ alkyloxyC₁₋₁₀ alkyl,

[0291] C₁₋₄ alkoxy C₁₋₄ alkyl,

[0292] -SO₂R^(2a) alkyl,

[0293] -SO₂R^(2a) wherein R^(2a) is aryl,

[0294] -SO_(2b) R wherein R^(2b) is heteroaryl,

[0295] -NR^(2C)R^(2D) wherein R^(2c) and R^(2d) are independently selected from H, C₁₋₈ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkyloxyCl₆ alkyl, -C(O)C₁₋₄alkyl or R^(2c) and R^(2d) may join to form a heterocyclic ring having 0-3 heteroatoms selected from O, N or S,

[0296] -halogen,

[0297] -CN,

[0298] -C (O) NR^(2c)R^(2d),

[0299] -C(O)R wherein R is C₁₋₆ alkyl,

[0300] -C(O)OC₁₋₄ alkyl,

[0301] -C(O)O(CH₂)₂OR wherein R is C₁₋₃ alkyl,

[0302] -C(O)O(CH₂)₂-NHR wherein R is C₁₋₃ alkyl,

[0303] -C(O)O(CH₂)₂-NR²,

[0304] -C(O)OH,

[0305] -C(O)H,

[0306] -C(O)Ph,

[0307] -C(O)R′ wherein R′ is aryl, heteroaryl or carboalkoxy;

[0308] n is 0, 1 or 2;

[0309] R² is substituted with 0-3 substituents independently selected from R′, R″, R″′ wherein R′, R″ and R″′ are independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, hydroxyC₁ ₆ alkyl, C₁₋₆ alkyloxyC₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkyloxy, hydroxy, or

[0310] R² is substituted with 0-3 substituents independently selected from

[0311] halogen,

[0312] -CN,

[0313] -S(O)_(n)R^(2e) wherein R^(2e) is selected from C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkyloxy C₁₋₄alkyl, C₃₋₆ cycloalkyl;

[0314] -COR^(2f) wherein R^(2f) is selected from H, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkyloxy C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkylC₁₋₄ alkyl;

[0315] -CO₂R^(2f),

[0316] -NR^(2g)COR^(2f) wherein R^(2g) is selected from H, C₁₋₆ alkyl, C₃₋₇c-alkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl;

[0317] -N(COR^(2f))₂,

[0318] -NR^(2g)CONR^(2f)R^(2h), wherein R^(2h) is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy C₁₋₄ alkyl, C₃₋₆ cycloalkyl and C₃₋₆ cycloalkylC₁₋₆ alkyl;

[0319] -NR^(2g)CO₂R^(2e), -CONR^(2g)GR^(2h),

[0320] 1-morpholinyl,

[0321] 1-piperidinyl,

[0322] 1-piperazinyl,

[0323] and

[0324] C₃₋₈ cycloalkyl wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from -O-, -S(O)_(n)-, -NR^(2g)-, -NCO₂R^(2e) NCOR^(2e), and -NSO₂R^(2e); and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from R^(2g), CO₂R^(2e), COR^(2e) and SOR^(2e); or

[0325] the group R^(2,) R², R^(2k) , C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -OR^(2g), -NR^(2g)gR^(2h), C₁₋₆ alkylOR^(2g), and C₃₋₈ cycloalkyl which is substituted with 0-1 R^(2l) and in wich 0-1 carbons of C₄₋₈ cycloalkyl is replaced by -O-, wherein

[0326] R^(2i) is selected from aryl wherein aryl includes phenyl, naphthyl, indanyl and indenyl, each R^(2i) being substituted with 0-1 OR^(2m) and 0-5 substituents independently selected from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, nitro, -SH, -S(O)_(n)R^(2n), -COR^(2m), -OC(O)R², NR^(2g)COR^(2m), -N(COR^(2m))₂,

[0327] -NR^(2g)CONR^(2O)R^(2p), -NR^(2g)CO₂R^(2n), -NR^(2o)R^(2p) and -CONR^(2o)R^(2p);

[0328] R^(2j) is selected from heteroaryl wherein heteroaryl includes pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-s-oxide, 2,3-dihydro-benzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, nitro, OR^(2m), -SH, -S(O)_(n)R^(2h), -COR^(2m), -OC(O)R^(2h), -NR^(2g)COR^(2m), -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p), -NR^(2g)CO₂R^(2h), -NR^(2o)R^(2p) and -CONR^(2o)R^(2p) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(2g), CO_(n)R_(2e), COR^(2e) and SO₂R^(2e);

[0329] R^(2k) is heterocyclyl which is a saturated or partially saturated heteroaryl as defined for R^(2j), each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, nitro, -OR^(2m), -SH, S(O)_(n)R^(2h), -COR^(2m), -OC(O)R^(2h), -NR^(2g)COR^(2m), -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p), NR^(2g)COR^(2h), -NR^(2o)R^(2p) and -CONR^(2o)R^(2p) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(2f), CO₂R^(2e), COR^(2e) and SO₂R^(2e);

[0330] wherein

[0331] R^(2l) is H, C₁₋₄ alkyl, C₃₋₆ cycloalky-C₁₋₄ alkyl and C₃₋₈ cycloalkyl;

[0332] R^(2m) is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl, C₁₋₂ alkyloxy C₁₋₂ alkyl, C₁₋₄ haloalkyl, R^(2q)S (O)_(n)-C₁₋₄ alkyl and R^(2r)R^(2s)N-C₂₋₄ alkyl;

[0333] R^(2n) is H, C₁₋₆ alkyl, C₃₁₀ cyloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkyloxy C₁₋₂ alkyl, and C₁₋₄ haloalkyl;

[0334] R^(2o) and R^(2p) are independently selected at each occurrence from H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆cycloalkyl C₁₋₆ alkyl and C₁₋₄ haloalkyl;

[0335] R^(2q) is selected from C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl- C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl), heteroaryl and heleroaryl (C₁₋₄ alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₃₋₄ haloalkyl, nitro, C₁₋₄ alkoxy C₁₋₄ haloalkoxy, and dimethylamino;

[0336] R^(2r)R^(2s) taken together with the N form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl wherein N₄ in l-piperiazinyl is substituted with 0-1 substituents selected from the group R^(2t), CO₂R^(2q), COR^(2q) and SO₂R^(2q);

[0337] R^(2t) is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy -C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl -C₁₋₆ alkyl, aryl, aryl (C₁₋₄ alkyl)-, heteroaryl and heteroaryl (C₁₋₄ alkyl);

[0338] R³ is selected from an aryl or heteroaryl group attached through an unsaturated carbon atom;

[0339] aryl is selected from phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkyloxy-C₁₋₄ alkyloxy, -OR^(2m), Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, -NO₂, -SH, -S(O)_(n)R^(2n), -COR^(2m), -COR^(2m), OC(O)R^(2n), NR^(2g)COR^(2m), -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p), -NR^(2g)CO^(2o)R^(2p) and CONR^(2o)R^(2p) and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, -CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl;

[0340] heteroaryl is selected from the group pyridyl, pyrimidyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzo-furanyl, 2,3-dihydrobenzothienyl, 2,3-dihydro-benzothienyl-S-oxide, 2,3-dihydrobenzothienyl-s-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substitued at 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, F, I, C₁₋₄ haloalkyl, -CN, NR^(2g)R^(2h), nitro, -OR^(2m), -SH -S(O)_(n)R^(2n), COR^(2m), -CO₂R^(2m), -OC(O)R^(2n), -NR^(2g)COR^(2m), -N(COR^(2m))_(n), NR^(2g)CONR^(2o)R^(2p) and each heteroaryl being substituted at any nitrogen atom with 0-1 substituents selected from the group R^(2g), CO₂R^(3a), COR^(3a) and SO₂R^(3a) wherein,

[0341] R^(3a) is selected from the group C₁₋₆ alkyl, C₁₋₄ cycloalkyl-C₁₋₆ alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₃₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino; R⁴ and R¹ are independently selected at each occurrence from H, Br, Cl, F, I, -CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, amino, C₁₋₄ alkylamino, (C₁₋₄ alkyl)₂ amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group consisting of C₁₋₇ alkyl, C₃₋₈ cycloalkyl, Br, Cl, F, I, -C(O)H, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkylamino and (C₁₋₄ alkyl)₂ amino and wherein R⁴ and R⁵ non-phenyl groups may be substituted with 0-5 substituents selected from OH, halogen, -C(O)H, -OC₁₋₆-alkyl and C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₇ c-alkyl, C₁₋₆ alkyl(OH)_(n)CO₂R wherein R is H or C₁₋₆ alkyl, C₁₋₆ alkyl(OH)_(n), wherein n is 0-3 or R⁴ and R⁵ may join together to form a C₃₋₆ alkylene chain.

[0342] [13] The present invention also relates to a method as described directly above in group [12] wherein

[0343] R¹ is selected from C₁₋₆ alkyl, C₃₋₆cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, -XR^(1c) wherein R¹ is substituted with 0-6 substituents selected from halogen, C, alkyl or C₁₋₄ haloalkyl;

[0344] R² is selected from substituted-C₁₋₁₀ alkyl, branched C₃₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl,-NR^(2c)R^(2d) wherein, in the case of substituted-C₁₋₁₀ alkyl, 1-3 substitutents are independently selected from the group R^(2i), R^(2j), R^(2k), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, OR^(2g), -NR^(2g)R^(2h), -C₁₋₆ alkylOR^(2g) and C₃₋₈ cycloalkyl which is substituted with 0-1 R^(2l) and in wich 0-1 carbons of C₄₋₈ cycloalkyl is replacedby -O- and wherein the R² groups, other than substituted-C₁₋₁₀ alkyl, are substituted with 0-3 substituents independently selected from the group R^(2i), R^(2j), R^(2k), C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -OR^(2g), NR^(2g)R^(2h), -C₁₋₆ alkylOR^(2g), and C₃₋₈ cycloalkyl which is substituted with 0-1 R^(2l) and in wich 0-1 carbons of C₄₋₈ cycloalkyl is replaced by -O-.

[0345] [₁₋₄] The present invention also relates to a method described directly above in [12] or [13] wherein R³ is selected from an aryl group selected from phenyl or substituted versions thereof or a heteroaryl group selected from pyridyl or substituted versions thereof.

[0346] [15] The present invention relates to a method described directly above in groups [12]-[₁₋₄] wherein R³ is substituted with 0-4 substituents independently selected from halogen, C₁₋₄ alkyloxy, C₁₋₆ alkyl or NR′R″ wherein R¹ and R″ are independently selected from H or C₁₋₆ alkyl.

[0347] [₁₋₆] The present invention preferrably relates to a method as described directly above in groups [12]-[15] wherein R³ is selected from 2,4-dichlorophenyl, 2-chloro-4-methoxyphenyl, 2,4,6-trimethylphenyl, 2,4,6- trimethoxyphenyl, 2-dimethylamino-4-methyl-pyridin-5-yl, 2,4-dichloro-5-fluorophenyl, 2-chloro-4-methoxy-5-fluorophenyl, 2-chloro-4,5-dimethoxyphenyl or 2-chloro-4,5-dimethoxyphenyl.

[0348] [17] The present invention also preferrably relates to a method as described.in groups [13]-[15] wherein R² is selected from C₁ alkyl of the formula -CR′R″R″′ wherein R′, R″ and R″′ are independently selected from H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, hydroxyC₁₋₆ alkyl, C₁₋₆ alkyloxyCl₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkyloxy, hydroxy, with the proviso that each of R′,R″ and R″′ cannot be H;

[0349] or R² is selected from NR′R″ wherein R′ and R″ are independently selected from H or C₁₋₆ alkyl.

[0350] [18] The present invention preferrably relates to a method according to groups [13]-[17] wherein R³ is selected from an aryl or heteroaryl group attached through an unsaturated carbon atom wherein, aryl is phenyl, each phenyl being substituted with 0-5 substituents independently selected at each occurrence from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkyloxy-C₁₋₄ alkyloxy, -OR^(2m), Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, -NO_(2,) -SH, -S(O)_(n)R^(2n), -COR^(2m) ₁ -CO₂R^(2m), -OC(O)R^(2n), -NR^(2o)COR^(2p) -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p), -NR^(2g)CO₂R^(2h), -NR^(2o)R^(2p) and CONR^(2o)R^(2p) and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, -CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl and wherein, heteroaryl is selected at each occurrence from pyridyl, each pyridyl being substitued at 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, F, I, C₁₋₄ haloalkyl, -CN, nitro, -OR^(2m), -SH, -S(O)_(n)R^(2n), COR^(2m), -CO₂R^(2m), -OC(O)R^(2n), NR^(2g)COR^(2m), -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p) and each pyridyl being substituted at any nitrogen atom with 0-1 substituents selected from the group R^(2g), CO₂R^(3a), COR^(3a) and SO₂R^(3a).

[0351] [19] The present invention preferrably relates to a method of antagonizing a CRF-1 receptor in mammals including humans wherein binding to the receptor causes and ultimately results in the treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of formula (I)

[0352] or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein

[0353] R¹ is selected from C₁₋₆ alkyl, C₁₋₆alkyloxy, -SH or OH;

[0354] R² is selected from C₁₋₄ alkyl which is unsubstituted or substituted with 1-4 substitutents selected from C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkylOR^(2g), C₂₋₆ alkenyl or OR^(2g) wherein R is H or C₁₋₆ alkyl;

[0355] R³ is selected from an aryl or heteroaryl group bonded through an unsaturated carbon atom that is unsubstituted or substituted with 1-4 substituents selected from Cl, F, I, Br, -OH, CF₃, S(O)_(n)C₁₋₆ alkyl, -OC₁₋₆ alkyl, C₁₋₆ alkyl or NR^(2g)R^(2h) wherein R^(2g) and R^(2h) are independently selected from H or C₁₋₆ alkyl;

[0356] R⁴ and R⁵ are independently selected from H, C₁₋₆ alkyl or C₁₋₆ alkyloxy.

[0357] [20] The present invention also relates to a method according to group [19] wherein R³ is substituted with 2-4 substituents.

[0358] [21] The present invention also relates to a method according to group [19]-[20] wherein R² is substituted with 1-4 substituents.

[0359] [22] The present invention also relates to a method according to group [19]-[21] using the formulae shown in Table 1.

[0360] [23] The present invention also provides pharmaceutical compositions comprising compounds of Formula (1) with the variables as recited above in group [1] and [1′] with the proviso that the compounds excluded in proviso (d) in group [1] are included herein and a pharmaceutically acceptable carrier.

[0361] [24] The preferred pharmaceutical compositions include those compounds as shown in groups [1′] and [2]-[ll] along with a pharmaceutically acceptable carrier.

[0362] [25] The present invention also relates to a compound of the formulae shown below having the variables recited above in groups [1′] and [1]-[24]:

[0363] except that the provisos listed in group I are not included for the compounds of formula II and III.

[0364] [26] The present invention further comprises a compound of formula II or III in combination with a pharmaceutically acceptable excipient to form a pharmaceutical composition.

[0365] [27] The present invention further relates to a method of treating CRF related disorders or conditions or use in therapy of compounds of formula II or III comprising administering a compound of formula II or III with the variables for R¹-R⁵ as shown above in groups [1′] and

[0366] [1]-[24] to a patient in need of treatment thereof.

[0367] Many compounds of this invention have one or more asymmetric centers or planes. Unless otherwise indicated, all chiral (enantiomeric and diastereomeric) and racemic forms are included in the present invention. Many geometric isomers of olefins, C═N double bonds, and the like can also be present in the compounds, and all such stable isomers are contemplated in the present invention. The compounds may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis from optically active starting materials. All chiral, (enantiomeric and diastereomeric) and racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.

[0368] The term “alkyl”, unless otherwise specified, includes both branched and straight-chain alkyl having the specified number of carbon atoms. “Alkenyl” includes hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl, and the like. “Alkynyl” includes hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like. “Haloalkyl” is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms, substituted with 1 or more halogen; “alkoxy” represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; “cycloalkyl” is intended to include saturated ring groups, including mono-,bi- or poly-cyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and so forth. “Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.

[0369] The term “substituted”, as used herein, means that aone or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom s normal valency is not exceeded, and that the substitution results in a stable compound. When a substitent is keto (i.e., ═0), then 2 hydrogens on the atom are replaced.

[0370] Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0371] The term “pharmaceutically acceptable salts” includes acid or base salts of the compounds of formulas (I). Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.

[0372] Pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.

[0373] “Prodrugs” are considered to be any covalently bonded carriers which release the active parent drug of formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of formula (I) are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of formulas (I) and the like.

[0374] The term “therapeutically effective amount” of a compound of this invention means an amount effective to antagonize abnormal level of CRF or treat the symptoms of affective disorder, anxiety, depression, immunological, cardiovascular or heart-related diseases and colonic hypersensitivity associated with psychopathological disturbance and stress in a host.

[0375] The term “registry reference” refers to computer search generated sources of known chemical structures as identified by specific structure herein.

[0376] Compounds prepared according to the synthetic schemes and examples include, without limitation, those compounds specifically set forth in Table 1, hereinbelow, as well as the following:

[0377] 7-(2,4-dichloro-5-fluorophenyl)-2-ethyl-3-(2-pentyl)-pyrazolo[1,5-a]pyrimidine

[0378] 7-(2,4-dichlorophenyl)-2-ethyl-6-methyl-3-(2-pentyl)-pyrazolo[1,5-a]pyrimidine

[0379] 7-(2-chloro-4-methoxyphenyl)-2-ethyl-3-(2-pentyl)pyrazolo[1,5-a]pyrimidine

[0380] 2-ethyl-3-(2-pentyl)-7-(2,4,6-trimethylphenyl)-pyrazolo[1,5-a]pyrimidine

[0381] 2-ethyl-3-(2-pentyl)-7-(2,4,6-trimethoxyphenyl)-pyrazolo[1,5-a]pyrimidine

[0382] 7-(2,4-dichlorophenyl)-2-ethyl-3-(2-pentyl)pyrazolo[1,5-a]pyrimidine

[0383] 7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyrimidine-3-carboxaldehyde

[0384] 7-(2,4-dichlorophenyl)-2-ethyl-3-(1-hydroxyethyl)-pyrazolo[1,5-a]pyrimidine

[0385] 7-(2,4-dichlorophenyl)-3-(1-ethoxyethyl)-2-ethyl-pyrazolo[1,5-a]pyrimidine

[0386] 7-(2,4-dichlorophenyl)-3-(1-ethoxyethyl)-2-ethylpyrazolo[1,5-a]pyrimidine

[0387] 2-ethyl-7-(2-methyl-4-methoxyphenyl)-3-(3-pentyl)-pyrazolo[1,5-a]pyrimidine

[0388] 2-ethyl-7-(2-methyl-4-methoxyphenyl)-3-(2-pentyl)-pyrazolo[1,5-a]pyrimidine

[0389] 7-(2,4-dimethylphenyl)-2-ethyl-3-(2-pentyl)-pyrazolo[1,5-a]pyrimidine

[0390] 7-(2,4-dichlorophenyl)-2-ethyl-5-methylthio-3-(2-pentyl)-pyrazolo[1,5-a]pyrimidine

[0391] 7-(2,4-dichlorophenyl)-2-ethyl-3-(6-methyl-5-hepten-2-yl)-pyrazolo[1,5-a]pyrimidine

[0392] 7-(2,4-dichlorophenyl)-2-ethyl-3-(1-hydroxy-4-pentyl)-pyrazolo[1,5-a]pyrimidine

[0393] 7-(4-difluoromethoxy-2-methyl)-2-ethyl-3-(3-pentyl)pyrazolo[1,5-a]pyrimidine

[0394] 7-(4-difluoromethoxy-2-methyl)-2-ethyl-3-(2-pentyl)pyrazolo[1,5-a]pyrimidine

[0395] 7-(2-chloro-4-difluoromethoxyphenyl)-2-ethyl-3-(3-pentyl)pyrazolo[1,5-a]pyrimidine

[0396] 7-(2-chloro-4-difluoromethoxyphenyl)-2-ethyl-3-(2-pentyl)pyrazolo[1,5-a]pyrimidine

[0397] 7-(2,4-dimethylphenyl)-2-ethyl-3-(3-pentyl)pyrazolo[1,5-a]pyrimidine

[0398] 4-(7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyrimidinyl)pentanoic acid

[0399] 4-(7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyrimidinyl)-N-methylpentanamide

[0400] 3-(5-(benzoxazol-2-ylthio)-2-pentyl)-7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a] pyrimidine

[0401] 3-(5-(benzoxazolidinethione-3-yl)-2-pentyl)-7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyrimidine

[0402] 7-(2,4-dichlorophenyl)-2-ethyl-3-(1-hydroxy-2-propyl)-pyrazolo[1,5-a]pyrimidine

[0403] 7-(2,4-dichlorophenyl)-3-(1-ethoxy-2-propyl)-2-ethyl-pyrazolo[1,5-a]pyrimidine

[0404] 3-(1-acetoxy-2-propyl)-7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyrimidine

[0405] 3-(1-acetoxy-2-butyl)-7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyrimidine

[0406] 7-(2,4-dichlorophenyl)-2-ethyl-3-(1-hydroxy-3-butyl)pyrazolo[1,5-a]pyrimidine

[0407] 7-(2,4-dichlorophenyl)-2-ethyl-3-(1-methoxy-3-butyl)pyrazolo[1,5-a]pyrimidine

[0408] 7-(2,4-dichiorophenyl)-2-ethyl-3-(3-heptyl)-pyrazolo[1,5-a]pyrimidine

[0409] 7-(2,4-dichlorophenyl)-2-ethyl-3-(3-heptyl)-6-methyl-pyrazolo[1,5-alpyrimidine

[0410] 2-ethyl-3-(3-heptyl)-7-(2,4,6-trimethylphenyl)-pyrazolo[1,5-a]pyrimidine

[0411] 7-(2,4-dichlorophenyl)-2-ethyl-3-(3-pentyl)-pyrazolo[1,5-a]pyrimidine

[0412] 7-(2,4-dichlorophenyl)-2-ethyl-3-(3-pentyl)-6-methyl-pyrazolo[1,5-a]pyrimidine

[0413] 2-ethyl-3-(3-pentyl)-7-(2,4,6-trimethylphenyl)-pyrazolo[1,5-a]pyrimidine

[0414] 2-ethyl-3-(3-pentyl)-7-(2,4,6-trimethoxyphenyl)-pyrazolo[1,5-a]pyrimidine

Synthesis

[0415] Compounds of formula (I) can be prepared by the following synthetic routes and schemes. Where a detailed description is not provided, it is assumed that those skilled in the art of organic synthesis will readily understand the meaning.

[0416] Synthesis of compounds of formula (I) may be prepared by the reaction shown in Scheme 1.

[0417] The embodiment of this invention concerning compounds of Formula (I) with the structure

[0418] may be prepared according to the following methods:

[0419] The pyrazolo[1,5-a]pyrimidine ring system is best prepared by the condensation reaction of a 3-aminopyrazole (1-A, Scheme 1A) with a compound of formula 1-B. Here, Z is ethoxy or dimethylamino, and compound 1-B may be prepared by the reaction of a compound of formula R³C(═O)CH₂R⁶ with a reagent of formula R⁵C(Z) (OEt)₂. These types of reactions are normally done by heating the two compounds (as a 1:1 mixture) without solvent, and distilling off the volatile components after the reaction is complete. The reaction between 1-A and 1-B is conveniently performed in a solvent such as acetic acid with heating; the acetic acid acts as both solvent and catalyst for the condensation.

[0420] Preparation of the pyrazoles can begin with the acylation of a nitrile compound 1-C (Scheme 1B). Normally, a strong base, such as lithium diisopropylamide, is used to deprotonate the nitrile, and the resulting anionic intermediate is treated with a carboxylic ester R¹CO₂Et or

[0421] acid chloride R¹COCl to generate the ketonitrile 1-D. Condensation of this compound with hydrazine then gives the aminopyrazole. This reaction may be performed in refluxing alcoholic solvent with the optional presence of an acid catalyst, such as acetic acid. Heteroatomic versions of this route are possible. Aminopyrazoles with an R¹ group wherein R¹=R^(1a)O may be prepared by starting with cyanoacetic esters like 1-E, which react with hydrazine to afford 3-amino-5-hydroxypyrazole 1-F. Cyclization with reagent 1-B and O-alkylation with a reagent RlaX, wherein X is a halide or pseudohalide group, gives compound 1-G. Finally, strong base treatment of aminonitrile 1-H, usually in the presence of a solvent mixture such as THF/HMPA, followed by acylation and ring-forming, gives diamine 1-K.

[0422] Scheme 1C shows one application of a variation involving a group G (carboalkoxy or CN) which can serve as a functional handle for various R² substitutions. Since G is activating, the acylation of 1-L to give 1-M may not require as strong a base as is used for the transformation of 1-C to 1-D; a reagent such as an orthoester may also be used. Subsequent ring condensations to 1-N and then to 1-P proceed as described earlier. Then, the group G is converted to the R² group of choice wherein R² and substituted versions thereof is as defined in the claims and as above in the specification; the following method is one example. Use of a reducing agent such as diisobutylaluminum hydride in a solvent like toluene or dichloromethane at low temperatures can be used to obtain the aldehyde 1-Q. The aldehyde may be allowed to react with organometallic reagents such as the Grignard reagent R^(2a)MgBr to afford the alcohol 1-R. The hydroxy group may then be O-alkylated (typically using a reagent R^(2c)X and a base such as sodium hydride in a polar aprotic solvent such as DMF) to give the compound 1-S. Other such manipulations of the G group should be familiar to those skilled in the art of organic synthesis.

[0423] Similarly, the remaining variables in the starting materials described above such as R¹ or R³ are determined based upon the desired target moiety. Thus, varying the ketone 1-B with respect to the aryl or heteroaryl group R³ permits synthesis of a compound of formula I having R³ as the desired heteroaryl or aryl group and substituted versions thereof as recited in the claims and above text and as further shown in the examples and table before the appended claims.

[0424] The synthesis of compounds of formula II or III may be accomplished by the general schemes shown below in Scheme 2 and in Scheme 3.

[0425] The variables for R¹ -R⁵ are selected from those variables as defined in any of the groups [1]-[24]. The compound of formula II is prepared by starting with the acyclic triketo intermediate shown above which is reacted with reagent a to form the bicyclic intermediate which is then treated with the grignard reagent b to form a compound of formula II.

[0426] The variables for R¹-R⁵ in Scheme 3 are selected from those described in groups [1]-[24]. Compounds II and III with the variables as defined above are useful as CRF antagonists.

Utility CRF-R¹ Receptor Binding Assay for the Evaluation of Biological Activity Radioligand binding experiments

[0427] Compounds of the invention were tested for in vitro activity as CRF receptor antagonists. The tests described below demonstrated that the examples tested had K_(i)s of 10,000 nM or less a nd are thus useful as CRF receptor antagonists. Preferred antagonists have or will have a K_(i) of 1,000 nM or less. Radioligand binding experiments were performed with membranes from rat frontal cortex to determine binding affinities (K_(i)′s) of test compounds for the rat CRHE receptor using a modified version of methods described earlier (see E. B. DeSouza, J. Neurosci, 7:88, 1987). Rat cortex was homogenized in tissue buffer (containing 50 mM HEPES, 10 mM MgCl₂, 2 mM EGTA, and 1 μg/ml each of aprotonin, leupeptin, and pepstatin, pH 7.0 @ 23° C.) using a Brinkman Polytron (PT-10, setting 6 for 10 sec). The homogenate was centrifuged at 48,000 ×g for 12 min and the resulting pellet was washed by two sequential re-suspension and centrifugation steps. The final pellet was suspended to tissue buffer to a working concentration of 0.1 mg/ml protein. Protein determinations were made using the bicinchoninic acid (BCA) assay (Pierce, Rockford, Ill.) with bovine serum albumin as the standard.

[0428] All test compounds were prepared in assay buffer, which was identical to the tissue buffer except for the inclusion of 0.15 mM bacitracin and 0.1% w/v ovalbumin. Binding assay were conducted in disposable polypropylene 96-well plates (Costar Corp., Cambridge, Mass.) and initiated by the addition of 100 μl membrane homogenate (containing 40-60 μg protein) to 200 μl of assay buffer containing radioligands (150 pM, final concentration, [¹²⁵I] tyr^(o) ovine CRH; New England Nuclear, Mass.) and competing test compounds. Specific binding was determined in the presence of 10 μM α-helical CRH. Competition experiments were conducted using 12 concentrations of ligand (ranging from 1×10⁻¹¹ to 1×10⁻⁵ M). The reactions mixtures were incubated to equilibrium for 2 hr at 23° C. and terminated by rapid filtration using a cell harvester (Inotech Biosystems Inc., Lansing, Mich.) over GFF glass-fibers (pre-soaked in 0.3 % v/v polyethyleneimine). Filters were rapidly washed 3× with 0.3 ml cold wash buffer (PBS, pH 7.0, containing 0.01% Triton X-100), dried, and counted in a gamma counter at 80% efficiency.

[0429] Binding affinities (K_(i)′s) of ligands for the CRH, receptor were calculated using the iterative nonlinear regression curve-fitting programs (LIGAND) of Munson and Rodbard (Anal. Biochem. 1980, 107, 220-239) or Prism (GraphPad Prism, San Diego, Calif.). Data were best-fit by the one-site/state competition equation.

Inhibition of CRF-Stimulated Adenylate Cyclase Activity

[0430] Inhibition of CRF-stimulated adenylate cyclase activity can be performed as described by G. Battaglia et al. Synapse 1:572 (1987). Briefly, assays are carried out at 37° C. for 10 min in 200 ml of buffer containing 100 mM Tris-HCl (pH 7.4 at 37° C.), 10 mM MgCl₂, 0.4 mM EGTA, 0.1% BSA, 1 mM isobutylmethylxanthine (IBMX), 250 units/ml phosphocreatine kinase, 5 mM creatine phosphate, 100 mM guanosine 5-triphosphate, 100 nM OCRF, antagonist peptides (concentration range 10⁻⁹ to ₁₀ ^(−6m)) and 0.8 mg original wet weight tissue (approximately 40-60 mg protein). Reactions are initiated by the addition of 1 mM ATP/³²P]ATP (approximately 2-4 mCi/tube) and terminated by the addition of 100 ml of 50 mM Tris-HCL, 45 mM ATP and 2% sodium dodecyl sulfate. In order to monitor the recovery of cAMP, 1 μl of [³H]cAMP (approximately 40,000 dpm) is added to each tube prior to separation. The separation of [³²P]cAMP from [³²P]ATP is performed by sequential elution over Dowex and alumina columns.

In vivo Biological Assay

[0431] The in vivo activity of the compounds of the present invention can be assessed using any one of the biological assays available and accepted within the art. Illustrative of these tests include the Acoustic Startle Assay, the Stair Climbing Test, and the Chronic Administration Assay. These and other models useful for the testing of compounds of the present invention have been outlined in C. W. Berridge and A. J. Dunn Brain Research Reviews 15:71 (1990). Compounds may be tested in any species of rodent or small mammal.

[0432] Compounds of this invention have utility in the treatment of inbalances associated with abnormal levels of corticotropin releasing factor in patients suffering from depression, affective disorders, and/or anxiety.

[0433] Compounds of this invention can be administered to treat these abnormalities by means that produce contact of the active agent with the agent s site of action in the body of a mammal. The compounds can be administered by any conventional means available for use in conjunction with pharmaceuticals either as individual therapeutic agent or in combination of therapeutic agents. They can be administered alone, but will generally be administered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice.

[0434] The dosage administered will vary depending on the use and known factors such as pharmacodynamic character of the particular agent, and its mode and route of administration; the recipient's age, weight, and health; nature and extent of symptoms; kind of concurrent treatment; frequency of treatment; and desired effect. For use in the treatment of said diseases or conditions, the compounds of this invention can be orally administered daily at a dosage of the active ingredient of 0.002 to 200 mg/kg of body weight. Ordinarily, a dose of 0.01 to 10 mg/kg in divided doses one to four times a day, or in sustained release formulation will be effective in obtaining the desired pharmacological effect.

[0435] Dosage forms (compositions) suitable for administration contain from about 1 mg to about 100 mg of active ingredient per unit. In these pharmaceutical compositions, the active ingredient will ordinarily be present in an amount of about 0.5 to 95% by weight based on the total weight of the composition.

[0436] The active ingredient can be administered orally is solid dosage forms, such as capsules, tablets and powders; or in liquid forms such as elixirs, syrups, and/or suspensions. The compounds of this invention can also be administered parenterally in sterile liquid dose formulations.

[0437] Gelatin capsules can be used to contain the active ingredient and a suitable carrier such as but not limited to lactose, starch, magnesium stearate, steric acid, or cellulose derivatives. Similar diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as sustained release products to provide for continuous release of medication over a period of time. Compressed tablets can be sugar-coated or film-coated to mask any unpleasant taste, or used to protect the active ingredients from the atmosphere, or to allow selective disintegration of the tablet in the gastrointestinal tract.

[0438] Liquid dose forms for oral administration can contain coloring or flavoring agents to increase patient acceptance.

[0439] In general, water, pharmaceutically acceptable oils, saline, aqueous dextrose (glucose), and related sugar solutions and glycols, such as propylene glycol or polyethylene glycol, are suitable carriers for parenteral solutions. Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing agents, and if necessary, butter substances. Antioxidizing agents, such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or in combination, are suitable stabilizing agents. Also used are citric acid and its salts, and EDTA. In addition, parenteral solutions can contain preservatives such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.

[0440] Suitable pharmaceutical carriers are described in “Remington's Pharmaceutical Sciences”, A. Osol, a standard reference in the field.

[0441] Useful pharmaceutical dosage-forms for administration of the compounds of this invention can be illustrated as follows:

Capsules

[0442] A large number of units capsules are prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg lactose, 50 mg cellulose, and 6 mg magnesium stearate.

Soft Gelatin Capsules

[0443] A mixture of active ingredient in a digestible oil such as soybean, cottonseed oil, or olive oil is prepared and injected by means of a positive displacement was pumped into gelatin to form soft gelatin capsules containing 100 mg of the active ingredient. The capsules were washed and dried.

Tablets

[0444] A large number of tablets are prepared by conventional procedures so that the dosage unit was 100 mg active ingredient, 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 275 mg of microcrystalline cellulose, 11 mg of starch, and 98.8 mg lactose. Appropriate coatings may be applied to increase palatability or delayed adsorption.

[0445] The preferred indication and use of the compounds and compositions of the invention is in the treatment of depression or anxiety.

[0446] The compounds of this invention may also be used as reagents or standards in the biochemical study of neurological function, dysfunction, and disease.

[0447] The following examples are provided to describe the invention in further detail. These examples, which set forth the best mode presently contemplated for carrying out the invention, are intended to illustrate and not to limit the invention.

EXAMPLES

[0448] The following specific synthetic example describes the procedures which, when applied to appropriately substituted substrates, may be employed in the synthesis of the compounds in Table 1.

Example 1 Preparation of 7-(2,4-dichlorophenyl)-2-ethyl-3-(3-Pentyl)pvrazolorl,5-alpyrimidine

[0449] Part A. A mixture of 2-ethyl-l-bromobutane (10.0 mL, 71.4 mmol), potassium cyanide (_(1-4.0) g, 215 mmol) and aliquat 336 (10 drops) in 50 mL water was heated to reflux overnight with vigorous stirring. The mixture was cooled, and extracted with dichloromethane (2×50 mL). The extracts were combined, dried over magnesium sulfate, filtered and evaporated. The residual liquid was distilled bulb-to-bulb to afford pure product, 3-ethylpentanenitrile (5.50 g, 49.5 mmol, 69%). b.p. 40-45 °C. (5 mm Hg). Spectral data: ¹H NMR (300 MHz, CDCl₃): δ22.33 (2H, d, J=5.8 Hz), 1.62-1.36 (5H, m), 0.92 (6H, t, J=7.3 Hz). MS (H₂O-GC/MS): m/e 112 (100).

[0450] Part B. A solution of diisopropylamine (7.50 mL, 57.2 mmol) in THF (100 mL) was cooled to -78° C., and treated with n-butyllithium (34.0 mL of a 1.6 M solution in hexane). The solution was warmed briefly to 0° C., and then recooled to −78° C. The nitrile compound from Part A was then added by syringe, and the solution was allowed to stir for 1 hour. Then, ethyl propionate (6.50 mL, 56.7 mmol) was added by syringe, and the resulting mixture was allowed to stir and warm to ambient temperature for 12 hours. It was poured into 200 mL of satd. aq. NH₄Cl solution, and this was extracted with ethyl acetate (2×200 mL). The extracts were combined, dried over magnesium sulfate, filtered and evaporated. The residual oil was separated by column chromatography (silica gel, 10:90 ethyl acetate-hexane) to afford the product, 4-cyano-5-ethyl-3-heptanone, as an oil 4.06 g, 24.3 mmol, 49%). TLC R_(F) 0.47 (20:80 ethyl acetate-hexane). Spectral data: ¹H NMR (300 MHz, CDC₁ ₃): 63.49 (1H, d, J=4.4 Hz), 2.74 (2H, q, J 7.3 Hz), 2.08-1.98 (1H, m), 1.70-1.58 (1H, m), 1.50-1.20 (3H, m), 1.12 (3H, t, J=7.3 Hz), 0.95 (3H, t, J=7.3 Hz), 0.91 (3H, t, J=7.3 Hz). MS (H₂O-GC/MS): m/e 167 (100).

[0451] Part C. A solution of the ketonitrile from Part B (4.06 g, 24.3 mmol), hydrazine hydrate (2.70 mL, 55.7 mmol) and acetic acid (5.00 mL, 83.7 mmol) in benzene (50 mL) was heated to reflux under a Dean-Stark trap with azeotropic distillation of water. After being heated for 12 hours, the mixture was cooled and poured into 100 mL 1 N aq. NaHCO₃ solution. This was extracted with ethyl acetate (2×100 mL), and the extracts were washed in sequence with brine, combined, dried over sodium sulfate, filtered and evaporated to afford sufficiently-pure product, 3-amino-5-ethyl-4-(3-pentyl)pyrazole, as a viscous oil (2.48 g, 13.7 mmol, 56%). Spectral data: ¹H NMR (300 MHz, CDC₁ ₃):6 3.48 (2H, br), 2.54 (2H, q, J=7.3 Hz), 2.25-2.1-4 (1H, m), 1.71-1.49 (4H, m), 1.20 (3H, t, J=7.3 Hz), 0.83 (6H, t, J=7.3 Hz), lH missing. MS (NH₃-CI): m/e ₁₋₈₃ (12), 182 (100).

[0452] Part D. A mixture of 2,4-dichloroacetophenone (10.0 g, 52.9 mmol) and dimethylformamide diethyl acetal (10.0 mL, 58.3 mmol) was heated to reflux for 12 hours, then cooled and evaporated under high vacuum. The residual oil was separated by column chromatography (silica gel, 1:1 ethyl acetate-hexane) to afford the product, 1-(2,4-dichlorobenzoyl)-2-(N,N-dimethylamino)ethene, as a viscous oil (12.11 g, 49.6 mmol, 94%). TLC R_(f) 0. 05 (20:80 ethyl acetate-hexane). Spectral data: ¹H NMR (300 MHz, CDC₁ ₃) :δ7.40 (1H, d, J=2.2 Hz), 7.38-7.23 (3H, m) , 5.33 (1H, d, J=12.4 Hz), 3.11 (3H, br s), 2.89 (3H, br s). MS (NH₃-CI): m/e 249 (1), 248 (10), 247 (8), 246 (64), 245 (₁₋₆), 244 (100).

[0453] Part E. A solution of the product of Part C (2.25 g, 1.38 mmol) and that of Part D (0.337 g, 1.38 mmol) in acetic acid (5 mL) was heated to reflux for 10 hours, then cooled, and poured into water. This was neutralized by the addition of solid sodium bicarbonate until the evolution of CO₂ subsided. The resulting mixture was extracted with ethyl acetate (2×100 mL), and the extracts were washed with brine (100 mL), combined, dried over sodium sulfate, filtered and evaporated. The resulting mixture of regioisomeric products (ca. 5:1 estimated by TLC visualization) were separated by column chromatography (silica gel, 10:90 ethyl acetate-hexane) to afford the major regioisomer as the more TLC-mobile product, which was the title compound. TLC R_(f) 0.32 (10:90 ethyl acetate-hexane). Spectral data: ¹H NMR (300 MHz, CDCl₃) : δ8.38 (1H, d, J=4.1 Hz), 7.58 (1H, d, J=2.0 Hz), 7.55 (1H, d, J=8.2 Hz), 7.41 (1H, dd, J=8.2, 2.0 Hz), 6.65 (1H, d, J=4.1 Hz), 2.79 (2H, q, J=7.7 Hz), 2.78-2.68 (1H, m), 2.03-1.79 (4H, m), 1.25 (3H, t, J=7.7 Hz), 0.83 (6H, t, J=7.3 Hz). MS (NH₃-CI): m/e 367 (2), 366 (11), 365 (15), 364 (65), 363 (25), 362 (100). Analysis calcld for C₁₉H₂₁Cl₂N₃: C, 62.99; H, 5.84; N, 11.60; found: C, 62.97; H, 5.74; N, 11.49.

[0454] Examples 2-30 were prepared and/or may be prepared in an analogous fashion.

Example 31 Preparation of 7-(2,4-dichlorophenyl)-3-(N,N-diethylamino)-2-ethylpyrazolorl,5-alpyrimidine

[0455] Part A. A solution of diisopropylamine (10.0 mL, 76.3 mmol) in THF (60 mL) was cooled to −78° C., and treated with n-butyllithium (50.0 mL of a 1.6 M solution in hexane). The solution was warmed briefly to 0° C., and then recooled to

[0456] −78°C. To this was added first, N,N′-dimethylpropyleneurea as cosolvent (15 mL), then, diethylaminoacetontrile (10.0 mL, 74.1 mmol), and the solution was allowed to stir for 1 hour. Then, ethyl propionate (10.0 mL, 87.2 mmol) was added by syringe, and the resulting mixture was allowed to stir and warm to ambient temperature for 12 hours. It was poured into 200 mL of satd. aq. NH₄Cl solution, and this was extracted with ethyl acetate (2×200 mL). The extracts were combined, dried over magnesium sulfate, filtered and evaporated. The residual oil was separated by column chromatography (silica gel, 20:80 ethyl acetate-hexane) to afford the product, 2-(N,N-diethylamino)-3-oxopentanenitrile, as an oil (5.31 g, 31.6 mmol, 43%).

[0457] Part B. A solution of the ketonitrile from Part A, hydrazine hydrate (3.00 mL, 61.9 mol) and acetic acid (6.00 mL, 104 mmol) in benzene (100 mL) was heated to reflux under a Dean-Stark trap with azeotropic removal of water for a period of ₁₋₄ hours. Excess hydrazine (2 mL) and excess acetic acid (5 mL) were then added, and refluxing was allowed to continue for 20 hours. The solution was cooled and poured into 200 mL 1 N aq. NaHCO₃ solution. This was extracted with ethyl acetate (2×200 mL), and the extracts were washed in sequence with brine, combined, dried over sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, 30:70 ethyl acetate to remove unreacted starting material, then ethyl acetate) to afford the product, 3-amino-4-(N,N-diethylamino)-5-ethylpyrazole, as a viscous oil which darkens in air (750 mg, 4.41 mmol, 15%).

[0458] Part C. A solution of the diamine from Part B (300 mg, 1.76 mmol) and 1-(2,4-dichlorobenzoyl)-2-(N,N-dimethylamino)ethene (470 mg, 1.93 mmol) in acetic acid (5 mL) was heated to 100° C. for 10 hours, then cooled and poured into satd. aq. NaHCO₃ solution (100 mL). This mixture was extracted with ethyl acetate (2×100 mL), and the extracts were washed with brine, combined, dried over sodium sulfate, filtered and evaporated. The residual oil was separated by columnm chromatography (silica gel, 20:80 ethyl acetate-hexane) to afford the title product as a red oil (411 mg, 1.13 mmol, 64%). Spectral data: ¹H NMR (300 MHz, CDC₁ ₃) : δ8.38 (1H, d, J=4.0 Hz), 7.58 (1H, d, J=1.8 Hz), 7.56 (1H, d, J=8.4 Hz), 7.42 (1H, dd, J=8.4, 1.8 Hz), 6.65 (1H, d, J=4.0 Hz), 3.27 (4H, q, J=7.3 Hz), 2.80 (2H, q, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 1.00 (6H, t, J=7.3 Hz). MS (NH₃-CI): calculated for C₁₈H₂₁Cl₂N₄ 363.11-43, measured 363.11-46; mle 367 (6), 366 (14), 365 (81), 364 (28), 363 (100).

[0459] Examples 32-45 were and/or may be prepared in an analogous manner.

Examples 51 and 92 Preparation of 7-(2,4-dichlorophenyl)-2-hvdroxy-6-methyl-3-(3-pentvl)pvrazolofl,5-alpvrimidine (92) and 7-(2,4-dichlorophenyl)-2-methoxy-6-methyl-3-(3-Pentyl)pyrazoloF1,5-alpyrimidine (51)

[0460] Part A. A solution of triphenylphosphine (25.0 g, 95.3 mmol) in THF (200 mL) was cooled to -30° C., and diethyl azodicarboxylate (15.0 mL, 95.2 mmol) was slowly added dropwise in conc. THF solution. After the addition was complete, the mixture was treated with a THF solution of 3-pentanol (10.0 mL, 90.6 mmol) and ethyl cyanoacetate (10.0 mL, 92.1 mmol). The resulting mixture was allowed to stir and warm to ambient temperature for 12 hours, then was evaporated. The residual oil was separated by column chromatography (10:90 ethyl acetate-hexane) to afford the product, ethyl 2-cyano-3-ethylpentanoate, as a viscous oil (3.41 g, 18.6 mmol, 21%). TLC R_(F) 0.43 (20:80 ethyl acetate-hexane). Spectral data: ¹H NMR (300 MHz, CDCl₃) : δ4.27 (2H, q, J=7.0 Hz), 3.61 (1H, d, J=4.4 Hz), 2.04-1.93 (1H, m), 1.70-1.35 (4H, m), 1.33 (3H, t, J =7.0 Hz), 0.97 (3H, t, J=7.3 Hz), 0.94 (3H, t, J=7.3 Hz). MS (H₂O-GC/MS): m/e 185 (8), 184 (100).

[0461] Part B. A solution of the cyanoester from Part A and hydrazine hydrate (2.00 mL, 41.2 mmol) in ethanol (30 mL) was heated to reflux for 10 hours. The solution was cooled, and poured into water. This was extracted with ethyl acetate (2×100 mL), and the extracts were washed with brine, combined, dried over sodium sulfate, filtered and evaporated. The resulting oil was sufficiently pure product, 3-amino-5-hydroxy-4-(3-pentyl)pyrazole (1.29 g, 7.62 mmol, 41%).

[0462] Part C. A solution of the pyrazole compound from Part B (478 mg, 2.82 mmol) and 2-(2,4-dichlorobenzoyl)-1-(N,N-dimethylamino)-l-propene (729 mg, 2.82 mmol) in acetic acid (10 mL) was heated to reflux for 10 hours. The solution was cooled and poured into water (100 mL). This was neutralized by the addition of solid NaHCO₃. and the mixture was extracted with ethyl acetate (2×100 mL). The extracts were washed with brine, combined, dried over sodium sulfate, filtered and evaporated. The residue was separated by column chromatography (silica gel, 10:90 ethyl acetate-hexane) to give the compound of Example 92 as a solid (210 mg, 0.576 mmol, 20%). m.p. 227-228 OC. TLC R_(F) 0.46 (20:80 ethyl acetate-hexane). Spectral data: ¹H NMR (300 MHz, CDC₁ ₃): δ10.53 (1H, br s), 8.27 (1H, s) 7.63 (1H, d, J=2.2 Hz), 7.45 (1H, dd, J 8.4, 2.2 Hz), 7.25 (IH, d, J=8.4 Hz), 2.72-2.62 (1H, m), 2.02 (3H, s) , 1.77-1.65 (4H, m), 0.82 (6H, t, J 7.5 Hz). MS (ESI): m/e 366 (69), 364 (100).

[0463] Part D. A solution of the compound of Example 92 (31 mg, 0.085 mmol) and Proton-Sponge (20 mg, 0.093 mmol) in acetonitrile (2 mL) was cooled to 0° C., and treated with methyl methanetrifluorosulfonate (10 μL, 0.088 mmol). After stirring for 10 hours and warming to ambient temperature, the mixture was evaporated, and the residue was separated directly by column chromatography (silica gel, 10:90 ethyl acetate-hexane) to give the compound of Example 51 as a viscous oil (7 mg, 0.019 mmol, 22%). TLC R_(F) 0.55 (20:80 ethyl acetate-hexane). Spectral data: H NMR (300 MHz, CDC₁ ₃): δ8.27 (1H, s), 7.60 (1H, d, J=2.2 Hz), 7.43 (1H, dd, J=8.0, 2.0 Hz), 7.32 (1H, d, J=8.0 Hz), 3.84 (3H, s), 2.80-2.70 (1H, m), 2.08 (3H, s), 1.86-1.70 (4H, m), 0.82 (6H, t, J=7.4 Hz). MS (NH₃-CI): m/e 383 (2), 382 (12), 381 (₁₋₄), 380 (65), 379 (25), 378 (100).

[0464] Examples 52-90 and 92 were and/or may be prepared according to the procedures described above. The additional examples prepared or readily prepared (93-281) were (or may be) prepared according to the procedures described above and shown in the general schemes and described in the text. Table 1 shows the preferred compounds. TABLE 1

Ex m.p. No R¹ R² R⁴ R⁵ R³ ° C. 1 C₂H₅ (C₂H₅)₂CH H H 2,4-Cl₂—C₆H₃ oil^(a) 2 C₂H₅ (C₂H₅)₂CH H H 2-Cl-4-CH₃O—C₆H₃ 88-89 3 C₂H₅ (C₂H₅)₂CH H H 2,4,6-(CH₃)₃—C₆H₂ oil^(b) 4 C₂H₅ (C₂H₅)₂CH H H 2,4,6-(OCH₃)₃—C₆H₂ 166-167 5 C₂H₅ (C₂H₅)₂CH H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 6 C₂H₅ (C₂H₅)₂CH H CH₃ 2,4-Cl₂—C₆H₃ 90-91 7 C₂H₅ (C₂H₅)₂CH H CH₃ 2-Cl-4-CH₃O—C₆H₃ — 8 C₂H₅ (C₂H₅)₂CH H CH₃ 2,4,6-(CH₃)₃—C₆H₂ — 9 C₂H₅ (C₂H₅)₂CH H CH₃ 2,4,6-(OCH₃)₃—C₆H₂ — 10 C₂H₅ (C₂H₅)₂CH H CH₃ 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 11 C₂H₅ (C₂H₅)₂CH CH₃ H 2,4-Cl₂—C₆H₃ — 12 C₂H₅ (C₂H₅)₂CH CH₃ H 2-Cl-4-CH₃O—C₆H₃ — 13 C₂H₅ (C₂H₅)₂CH CH₃ H 2,4,6-(CH₃)₃—C₆H₂ — 14 C₂H₅ (C₂H₅)₂CH CH₃ H 2,4,6-(OCH₃)₃—C₆H₂ — 15 C₂H₅ (C₂H₅)₂CH CH₃ H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 16 C₂H₅ C₄H₉(C₂H₅)CH H H 2,4-Cl₂—C₆H₃ oil^(c) 17 C₂H₅ C₄H₉(C₂H₅)CH H H 2-Cl-4-CH₃O—C₆H₃ — 18 C₂H₅ C₄H₉(C₂H₅)CH H H 2,4,6-(CH₃)₃—C₆H₂ oil^(d) 19 C₂H₅ C₄H₉(C₂H₅)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 20 C₂H₅ C₄H₉(C₂H₅)CH H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 21 C₂H₅ C₄H₉(C₂H₅)CH H CH₃ 2,4-Cl₂—C₆H₃ 78-79 22 C₂H₅ C₄H₉(C₂H₅)CH H CH₃ 2-Cl-4-CH₃O—C₆H₃ — 23 C₂H₅ C₄H₉(C₂H₅)CH H CH₃ 2,4,6-(CH₃)₃—C₆H₂ — 24 C₂H₅ C₄H₉(C₂H₅)CH H CH₃ 2,4,6-(OCH₃)₃—C₆H₂ — 25 C₂H₅ C₄H₉(C₂H₅)CH H CH₃ 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 26 C₂H₅ C₄H₉(C₂H₅)CH CH₃ H 2,4-Cl₂—C₆H₃ — 27 C₂H₅ C₄H₉(C₂H₅)CH CH₃ H 2-Cl-4-CH₃O—C₆H₃ — 28 C₂H₅ C₄H₉(C₂H₅)CH CH₃ H 2,4,6-(CH₃)₃—C₆H₂ — 29 C₂H₅ C₄H₉(C₂H₅)CH CH₃ H 2,4,6-(OCH₃)₃—C₆H₂ — 30 C₂H₅ C₄H₉(C₂H₅)CH CH₃ H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 31 C₂H₅ (C₂H₅)₂N H H 2,4-Cl₂—C₆H₃ oil^(e) 32 C₂H₅ (C₂H₅)₂N H H 2-Cl-4-CH₃O—C₆H₃ 97-98 33 C₂H₅ (C₂H₅)₂N H H 2,4,6-(CH₃)₃—C₆H₂ — 34 C₂H₅ (C₂H₅)₂N H H 2,4,6-(OCH₃)₃—C₆H₂ — 35 C₂H₅ (C₂H₅)₂N H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 36 C₂H₅ (C₂H₅)₂N H CH₃ 2,4-Cl₂—C₆H₃ — 37 C₂H₅ (C₂H₅)₂N H CH₃ 2-Cl-4-CH₃O—C₆H₃ — 38 C₂H₅ (C₂H₅)₂N H CH₃ 2,4,6-(CH₃)₃—C₆H₂ — 39 C₂H₅ (C₂H₅)₂N H CH₃ 2,4,6-(OCH₃)₃—C₆H₂ — 40 C₂H₅ (C₂H₅)₂N H CH₃ 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 41 C₂H₅ (C₂H₅)₂N CH₃ H 2,4-Cl₂—C₆H₃ — 42 C₂H₅ (C₂H₅)₂N CH₃ H 2-Cl-4-CH₃O—C₆H₃ — 43 C₂H₅ (C₂H₅)₂N CH₃ H 2,4,6-(CH₃)₃—C₆H₂ — 44 C₂H₅ (C₂H₅)₂N CH₃ H 2,4,6-(OCH₃)₃—C₆H₂ — 45 C₂H₅ (C₂H₅)₂N CH₃ H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 46 OCH₃ (C₂H₅)₂N H H 2,4-Cl₂—C₆H₃ — 47 OCH₃ (C₂H₅)₂N H H 2-Cl-4-CH₃O—C₆H₃ — 48 OCH₃ (C₂H₅)₂N H H 2,4,6-(CH₃)₃—C₆H₃ — 49 OCH₃ (C₂H₅)₂N H H 2,4,6-(OCH₃)₃—C₆H₂ — 50 OCH₃ (C₂H₅)₂N H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 51 OCH₃ (C₂H₅)₂N H CH₃ 2,4-Cl₂—C₆H₃ oil^(f) 52 OCH₃ (C₂H₅)₂N H CH₃ 2-Cl-4-CH₃O—C₆H₃ — 53 OCH₃ (C₂H₅)₂N H CH₃ 2,4,6-(CH₃)₃—C₆H₂ — 54 OCH₃ (C₂H₅)₂N H CH₃ 2,4,6-(OCH₃)₃—C₆H₂ — 55 OCH₃ (C₂H₅)₂N H CH₃ 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 56 OCH₃ (C₂H₅)₂N CH₃ H 2,4-Cl₂—C₆H₃ — 57 OCH₃ (C₂H₅)₂N CH₃ H 2-Cl-4-CH₃O—C₆H₃ — 58 OCH₃ (C₂H₅)₂N CH₃ H 2,4,6-(CH₃)₃—C₆H₂ — 59 OCH₃ (C₂H₅)₂N CH₃ H 2,4,6-(OCH₃)₃—C₆H₂ — 60 OCH₃ (C₂H₅)₂N CH₃ H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 61 OCH₃ C₄H₉(C₂H₅)CH H H 2,4-Cl₂—C₆H₃ — 62 OCH₃ C₄H₉(C₂H₅)CH H H 2-Cl-4-CH₃O—C₆H₃ — 63 OCH₃ C₄H₉(C₂H₅)CH H H 2,4,6-(CH₃)₃—C₆H₂ — 64 OCH₃ C₄H₉(C₂H₅)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 65 OCH₃ C₄H₉(C₂H₅)CH H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 66 OCH₃ C₄H₉(C₂H₅)CH H CH₃ 2,4-Cl₂—C₆H₃ — 67 OCH₃ C₄H₉(C₂H₅)CH H CH₃ 2-Cl-4-CH₃O—C₆H₃ — 68 OCH₃ C₄H₉(C₂H₅)CH H CH₃ 2,4,6-(CH₃)₃—C₆H₂ — 69 OCH₃ C₄H₉(C₂H₅)CH H CH₃ 2,4,6-(OCH₃)₃—C₆H₂ — 70 OCH₃ C₄H₉(C₂H₅)CH H CH₃ 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 71 OCH₃ C₄H₉(C₂H₅)CH CH₃ H 2,4-Cl₂—C₆H₃ — 72 OCH₃ C₄H₉(C₂H₅)CH CH₃ H 2-Cl-4-CH₃O—C₆H₃ — 73 OCH₃ C₄H₉(C₂H₅)CH CH₃ H 2,4,6-(CH₃)₃—C₆H₂ — 74 OCH₃ C₄H₉(C₂H₅)CH CH₃ H 2,4,6-(OCH₃)₃—C₆H₂ — 75 OCH₃ C₄H₉(C₂H₅)CH CH₃ H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 76 OCH₃ (C₂H₅)₂N H H 2,4-Cl₂—C₆H₃ — 77 OCH₃ (C₂H₅)₂N H H 2-Cl-4-CH₃O—C₆H₃ — 78 OCH₃ (C₂H₅)₂N H H 2,4,6-(CH₃)₃—C₆H₂ — 79 OCH₃ (C₂H₅)₂N H H 2,4,6-(OCH₃)₃—C₆H₂ — 80 OCH₃ (C₂H₅)₂N H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 81 OCH₃ (C₂H₅)₂N H CH₃ 2,4-Cl₂—C₆H₃ — 82 OCH₃ (C₂H₅)₂N H CH₃ 2-Cl-4-CH₃O—C₆H₃ — 83 OCH₃ (C₂H₅)₂N H CH₃ 2,4,6-(CH₃)₃—C₆H₂ — 84 OCH₃ (C₂H₅)₂N H CH₃ 2,4,6-(OCH₃)₃—C₆H₂ — 85 OCH₃ (C₂H₅)₂N H CH₃ 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 86 OCH₃ (C₂H₅)₂N CH₃ H 2,4-Cl₂—C₆H₃ — 87 OCH₃ (C₂H₅)₂N CH₃ H 2-Cl-4-CH₃O—C₆H₃ — 88 OCH₃ (C₂H₅)₂N CH₃ H 2,4,6-(CH₃)₃—C₆H₂ — 89 OCH₃ (C₂H₅)₂N CH₃ H 2,4,6-(OCH₃)₃—C₆H₂ — 90 OCH₃ (C₂H₅)₂N CH₃ H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 91 CH₃ (C₂H₅)₂CH H H 2,4-Cl₂—C₆H₃ — 92 OH (C₂H₅)₂CH H CH₃ 2,4-Cl₂—C₆H₃ 227-228 93 C₂H₅ (C₂H₅)₂CH OCH₃ H 2,4-Cl₂—C₆H₃ — 94 C₂H₅ (C₂H₅)₂CH H OCH₃ 2,4-Cl₂—C₆H₃ — 95 C₂H₅ C₃H₇(CH₃)CH H H 2,4-Cl₂—C₆H₃ — 96 C₂H₅ CH₃(c-C₃H₅)CH H H 2,4-Cl₂—C₆H₃ — 97 C₂H₅ CH₃(c-C₄H₇)CH H H 2,4-Cl₂—C₆H₃ — 98 C₂H₅ (c-C₃H₅)₂CH H H 2,4-Cl₂—C₆H₃ — 99 C₂H₅ C₂H₅(c-C₃H₅)CH H H 2,4-Cl₂—C₆H₃ — 100 C₂H₅ CH₃(c-C₄H₇)CH H H 2,4-Cl₂—C₆H₃ — 101 C₂H₅ (HOCH₂)₂(CH₃)C H H 2,4-Cl₂—C₆H₃ — 102 C₂H₅ (HOCH₂)₂(CH₃)C H H 2-Cl-4-CH₃O—C₆H₃ — 103 C₂H₅ (HOCH₂)₂(CH₃)C H H 2,4,6-(CH₃)₃—C₆H₂ — 104 C₂H₅ (HOCH₂)₂(CH₃)C H H 2,4,6-(OCH₃)₃—C₆H₂ — 105 C₂H₅ (HOCH₂)₂(CH₃)C H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 106 C₂H₅ (HOCH₂)₂(CH₃)C H H 2,4-Cl₂-5-F—C₆H₂ — 107 C₂H₅ (HOCH₂)₂(CH₃)C H H 2-Cl-4-OCH₃-5-F — 108 C₂H₅ (HOCH₂)₂(CH₃)C H H 2-Cl-4,5-(OCH₃)₂ — 109 C₂H₅ (CH₃OCH₂)₂(CH₃)C H H 2,4-Cl₂—C₆H₃ — 110 C₂H₅ (CH₃OCH₂)₂(CH₃)C H H 2-Cl-4-CH₃O—C₆H₃ — 111 C₂H₅ (CH₃OCH₂)₂(CH₃)C H H 2,4,6-(CH₃)₃—C₆H₂ — 112 C₂H₅ (CH₃OCH₂)₂(CH₃)C H H 2,4,6-(OCH₃)₃—C₆H₂ — 113 C₂H₅ (CH₃OCH₂)₂(CH₃)C H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 114 C₂H₅ (CH₃OCH₂)₂(CH₃)C H H 2,4-Cl₂-5-F-C₆H₂ — 115 C₂H₅ (CH₃OCH₂)₂(CH₃)C H H 2-Cl-4-OCH₃-5-F — 116 C₂H₅ (CH₃OCH₂)₂(CH₃)C H H 2-Cl-4,5-(OCH₃)₂ — 117 C₂H₅ (H₂C═CH)₂(CH₃)C H H 2,4-Cl₂—C₆H₃ — 118 C₂H₅ (H₂C═CH)₂(CH₃)C H H 2-Cl-4-CH₃O—C₆H₃ — 119 C₂H₅ (H₂C═CH)₂(CH₃)C H H 2,4,6-(CH₃)₃—C₆H₂ — 120 C₂H₅ (H₂C═CH)₂(CH₃)C H H 2,4,6-(OCH₃)₃—C₆H₂ — 121 C₂H₅ (H₂C═CH)₂(CH₃)C H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 122 C₂H₅ (H₂C═CH)₂(CH₃)C H H 2,4-Cl₂-5-F-C₆H₂ — 123 C₂H₅ (H₂C═CH)₂(CH₃)C H H 2-Cl-4-OCH₃-5-F — 124 C₂H₅ (H₂C═CH)₂(CH₃)C H H 2-Cl-4,5-(OCH₃)₂ — 125 C₂H₅ (c-C₃H₅)₂(CH₃)C H H 2,4-Cl₂—C₆H₃ — 126 C₂H₅ (c-C₃H₅)₂(CH₃)C H H 2-Cl-4-CH₃O—C₆H₃ — 127 C₂H₅ (c-C₃H₅)₂(CH₃)C H H 2,4,6-(CH₃)₃—C₆H₂ — 128 C₂H₅ (c-C₃H₅)₂(CH₃)C H H 2,4,6-(OCH₃)₃—C₆H₂ — 129 C₂H₅ (c-C₃H₅)₂(CH₃)C H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 130 C₂H₅ (c-C₃H₅)₂(CH₃)C H H 2,4-Cl₂-5-F-C₆H₂ — 131 C₂H₅ (c-C₃H₅)₂(CH₃)C H H 2-Cl-4-OCH₃-5-F — 132 C₂H₅ (c-C₃H₅)₂(CH₃)C H H 2-Cl-4,5-(OCH₃)₂ — 133 C₂H₅ (C₂H₅)₂(OH)C H H 2,4-Cl₂—C₆H₃ — 134 C₂H₅ (C₂H₅)₂(OH)C H H 2-Cl-4-CH₃O—C₆H₃ — 135 C₂H₅ (C₂H₅)₂(OH)C H H 2,4,6-(CH₃)₃—C₆H₂ — 136 C₂H₅ (C₂H₅)₂(OH)C H H 2,4,6-(OCH₃)₃—C₆H₂ — 137 C₂H₅ (C₂H₅)₂(OH)C H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 138 C₂H₅ (C₂H₅)₂(OH)C H H 2,4-Cl₂-5-F-C₆H₂ — 139 C₂H₅ (C₂H₅)₂(OH)C H H 2-Cl-4-OCH₃-5-F — 140 C₂H₅ (C₂H₅)₂(OH)C H H 2-Cl-4,5-(OCH₃)₂ — 141 C₂H₅ C₂H₅(OCH₃)CH H H 2,4-Cl₂—C₆H₃ 142 C₂H₅ C₂H₅(OCH₃)CH H H 2-Cl-4-CH₃O—C₆H₃ — 143 C₂H₅ C₂H₅(OCH₃)CH H H 2,4,6-(CH₃)₃—C₆H₂ — 144 C₂H₅ C₂H₅(OCH₃)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 145 C₂H₅ C₂H₅(OCH₃)CH H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 146 C₂H₅ C₂H₅(OCH₃)CH H H 2,4-Cl₂-5-F-C₆H₂ — 147 C₂H₅ C₂H₅(OCH₃)CH H H 2-Cl-4-OCH₃-5-F — 148 C₂H₅ C₂H₅(OCH₃)CH H H 2-Cl-4,5-(OCH₃)₂ — 149 C₂H₅ (C₂H₅)₂CH H H 2,4-Cl₂-5-F-C₆H₂ oil 150 C₂H₅ (C₂H₅)₂CH H H 2-Cl-4-OCH₃-5-F — 151 C₂H₅ (C₂H₅)₂CH H H 2-Cl-4,5-(OCH₃)₂ — 152 C₂H₅ C₄H₉(C₂H₅)CH H H 2,4-Cl₂-5-F-C₆H₂ — 153 C₂H₅ C₄H₉(C₂H₅)CH H H 2-Cl-4-OCH₃-5-F — 154 C₂H₅ C₄H₉(C₂H₅)CH H H 2-Cl-4,5-(OCH₃)₂ — 155 OCH₃ (C₂H₅)₂CH H H 2,4-Cl₂-5-F-C₆H₂ oil^(g) 156 OCH₃ (C₂H₅)₂CH H H 2-Cl-4-OCH₃-5-F — 157 OCH₃ (C₂H₅)₂CH H H 2-Cl-4,5-(OCH₃)₂ — 158 C₂H₅ (C₂H₅)₂CH H H 2,4-Cl₂-5-F-C₆H₂ — 159 C₂H₅ (C₂H₅)₂CH H H 2-Cl-4-OCH₃-5-F — 160 C₂H₅ (C₂H₅)₂CH H H 2-Cl-4,5-(OCH₃)₂ — 161 C₂H₅ C₃H₇(CH₃)CH H H 2-Cl-4-CH₃O—C₆H₃ — 162 C₂H₅ C₃H₇(CH₃)CH H H 2,4,6-(CH₃)₃—C₆H₂ — 163 C₂H₅ C₃H₇(CH₃)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 164 C₂H₅ C₃H₇(CH₃)CH H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 165 C₂H₅ C₃H₇(CH₃)CH H H 2,4-Cl₂-5-F-C₆H₂ — 166 C₂H₅ C₃H₇(CH₃)CH H H 2-Cl-4-OCH₃-5-F — 167 C₂H₅ C₃H₇(CH₃)CH H H 2-Cl-4,5-(OCH₃)₂ — 168 C₂H₅ (C₂H₅)₂CH H H 2-CH₃-4-OCH₃-5-F—C₆H₂ — 169 OCH₃ (C₂H₅)₂CH H H 2-CH₃-4-OCH₃-5-F-C₆H₂ — 170 C₂H₅ C₄H₉(C₂H₅)CH H H 2-CH₃-4-OCH₃-5-F-C₆H₂ — 171 OCH₃ C₄H₉(C₂H₅)CH H H 2-CH₃-4-OCH₃-5-F-C₆H₂ — 172 C₂H₅ (C₂H₅)₂N H H 2-CH₃-4-OCH₃-5-F-C₆H₂ — 173 OCH₃ (C₂H₅)₂N H H 2-CH₃-4-OCH₃-5-F-C₆H₂ — 174 C₂H₅ C₃H₇(CH₃)CH H H 2-CH₃-4-OCH₃-5-F-C₆H₂ — 175 OCH₃ C₃H₇(CH₃)CH H H 2-CH₃-4-OCH₃-5-F-C₆H₂ — 176 C₂H₅ C₂H₅(OCH₃)CH H H 2-CH₃-4-OCH₃-5-F-C₆H₂ — 177 OCH₃ C₂H₅(OCH₃)CH H H 2-CH₃-4-OCH₃-5-F-C₆H₂ — 178 C₂H₅ (C₂H₅)₂CH H H 2-CH₃-4-OCH₃—C₆H₃ — 179 OCH₃ (C₂H₅)₂CH H H 2-CH₃-4-OCH₃—C₆H₃ — 180 C₂H₅ C₄H₉(C₂H₅)CH H H 2-CH₃-4-OCH₃—C₆H₃ — 181 OCH₃ C₄H₉(C₂H₅)CH H H 2-CH₃-4-OCH₃—C₆H₃ — 182 C₂H₅ (C₂H₅)₂N H H 2-CH₃-4-OCH₃—C₆H₃ — 183 OCH₃ (C₂H₅)₂N H H 2-CH₃-4-OCH₃—C₆H₃ — 184 C₂H₅ C₃H₇(CH₃)CH H H 2-CH₃-4-OCH₃—C₆H₃ — 185 OCH₃ C₃H₇(CH₃)CH H H 2-CH₃-4-OCH₃—C₆H₃ — 186 C₂H₅ C₂H₅(OCH₃)CH H H 2-CH₃-4-OCH₃—C₆H₃ — 187 OCH₃ C₂H₅(OCH₃)CH H H 2-CH₃-4-OCH₃—C₆H₃ — 188 C₂H₅ (C₂H₅)₂CH H H 2-CH₃-4-Cl—C₆H₃ — 189 OCH₃ (C₂H₅)₂CH H H 2-CH₃-4-Cl—C₆H₃ — 190 C₂H₅ C₄H₉(C₂H₅)CH H H 2-CH₃-4-Cl—C₆H₃ — 191 OCH₃ C₄H₉(C₂H₅)CH H H 2-CH₃-4-Cl—C₆H₃ — 192 C₂H₅ (C₂H₅)₂N H H 2-CH₃-4-Cl—C₆H₃ — 193 OCH₃ (C₂H₅)₂N H H 2-CH₃-4-Cl—C₆H₃ — 194 C₂H₅ C₃H₇(CH₃)CH H H 2-CH₃-4-Cl—C₆H₃ — 195 OCH₃ C₃H₇(CH₃)CH H H 2-CH₃-4-Cl—C₆H₃ — 196 C₂H₅ C₂H₅(OCH₃)CH H H 2-CH₃-4-Cl—C₆H₃ — 197 OCH₃ C₂H₅(OCH₃)CH H H 2-CH₃-4-Cl—C₆H₃ — 198 C₂H₅ CH₃OCH₂(CH₃)CH H H 2,4-Cl₂—C₆H₃ oil^(h) 199 C₂H₅ CH₃OCH₂(CH₃)CH H H 2-Cl-4-CH₃O—C₆H₃ — 200 C₂H₅ CH₃OCH₂(CH₃)CH H H 2,4,6-(CH₃)₃—C₆H₂ — 201 C₂H₅ CH₃OCH₂(CH₃)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 202 C₂H₅ CH₃OCH₂(CH₃)CH H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 203 C₂H₅ CH₃OCH₂(CH₃)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 204 C₂H₅ CH₃OCH₂(CH₃)CH H H 2,4-Cl₂-5-F-C₆H₂ — 205 C₂H₅ CH₃OCH₂(CH₃)CH H H 2-Cl-4-OCH₃-5-F — 206 C₂H₅ CH₃OCH₂(CH₃)CH H H 2-Cl-4,5-(OCH₃)₂ — 207 C₂H₅ CH₃OCH₂(CH₃)CH H H 2-CH₃-4-OCH₃-5-F—C₆H₂ — 208 C₂H₅ CH₃OCH₂(CH₃)CH H H 2-CH₃-4-OCH₃—C₆H₃ — 209 C₂H₅ CH₃OCH₂(CH₃)CH H H 2-CH₃-4-Cl—C₆H₃ — 210 OCH₃ CH₃OCH₂(CH₃)CH H H 2,4-Cl₂—C₆H₃ — 211 OCH₃ CH₃OCH₂(CH₃)CH H H 2-Cl-4-CH₃O—C₆H₃ — 212 OCH₃ CH₃OCH₂(CH₃)CH H H 2,4,6-(CH₃)₃—C₆H₂ — 213 OCH₃ CH₃OCH₂(CH₃)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 214 OCH₃ CH₃OCH₂(CH₃)CH H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 215 OCH₃ CH₃OCH₂(CH₃)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 216 OCH₃ CH₃OCH₂(CH₃)CH H H 2,4-Cl₂-5-F-C₆H₂ — 217 OCH₃ CH₃OCH₂(CH₃)CH H H 2-Cl-4-OCH₃-5-F — 218 OCH₃ CH₃OCH₂(CH₃)CH H H 2-Cl-4,5-(OCH₃)₂ — 219 OCH₃ CH₃OCH₂(CH₃)CH H H 2-CH₃-4-OCH₃-5-F—C₆H₂ — 220 OCH₃ CH₃OCH₂(CH₃)CH H H 2-CH₃-4-OCH₃—C₆H₃ — 221 OCH₃ CH₃OCH₂(CH₃)CH H H 2-CH₃-4-Cl—C₆H₃ — 222 C₂H₅ C₂H₅OCH₂(CH₃)CH H H 2,4-Cl₂—C₆H₃ — 223 C₂H₅ C₂H₅OCH₂(CH₃)CH H H 2-Cl-4-CH₃O—C₆H₃ — 224 C₂H₅ C₂H₅OCH₂(CH₃)CH H H 2,4,6-(CH₃)₃—C₆H₂ — 225 C₂H₅ C₂H₅OCH₂(CH₃)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 226 C₂H₅ C₂H₅OCH₂(CH₃)CH H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 227 C₂H₅ C₂H₅OCH₂(CH₃)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 228 C₂H₅ C₂H₅OCH₂(CH₃)CH H H 2,4-Cl₂-5-F—C₆H₂ — 229 C₂H₅ C₂H₅OCH₂(CH₃)CH H H 2-Cl-4-OCH₃-5-F — 230 C₂H₅ C₂H₅OCH₂(CH₃)CH H H 2-Cl-4,5-(OCH₃)₂ — 231 C₂H₅ C₂H₅OCH₂(CH₃)CH H H 2-CH₃-4-OCH₃-5-F—C₆H₂ — 232 C₂H₅ C₂H₅OCH₂(CH₃)CH H H 2-CH₃-4-OCH₃—C₆H₃ — 233 C₂H₅ C₂H₅OCH₂(CH₃)CH H H 2-CH₃-4-Cl—C₆H₃ — 234 OCH₃ C₂H₅OCH₂(CH₃)CH H H 2,4-Cl₂—C₆H₃ — 235 OCH₃ C₂H₅OCH₂(CH₃)CH H H 2-Cl-4-CH₃O—C₆H₃ — 236 OCH₃ C₂H₅OCH₂(CH₃)CH H H 2,4,6-(CH₃)₃—C₆H₂ — 237 OCH₃ C₂H₅OCH₂(CH₃)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 238 OCH₃ C₂H₅OCH₂(CH₃)CH H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 239 OCH₃ C₂H₅OCH₂(CH₃)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 240 OCH₃ C₂H₅OCH₂(CH₃)CH H H 2,4-Cl₂-5-F—C₆H₂ — 241 OCH₃ C₂H₅OCH₂(CH₃)CH H H 2-Cl-4-OCH₃-5-F — 242 OCH₃ C₂H₅OCH₂(CH₃)CH H H 2-Cl-4,5-(OCH₃)₂ — 243 OCH₃ C₂H₅OCH₂(CH₃)CH H H 2-CH₃-4-OCH₃-5-F—C₆H₂ — 244 OCH₃ C₂H₅OCH₂(CH₃)CH H H 2-CH₃-4-OCH₃—C₆H₃ — 245 OCH₃ C₂H₅OCH₂(CH₃)CH H H 2-CH₃-4-Cl—C₆H₃ — 246 C₂H₅ CH₃OCH₂(C₂H₅)CH H H 2,4-Cl₂—C₆H₃ — 247 C₂H₅ CH₃OCH₂(C₂H₅)CH H H 2-Cl-4-CH₃O—C₆H₃ — 248 C₂H₅ CH₃OCH₂(C₂H₅)CH H H 2,4,6-(CH₃)₃—C₆H₂ — 249 C₂H₅ CH₃OCH₂(C₂H₅)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 250 C₂H₅ CH₃OCH₂(C₂H₅)CH H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 251 C₂H₅ CH₃OCH₂(C₂H₅)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 252 C₂H₅ CH₃OCH₂(C₂H₅)CH H H 2,4-Cl₂-5-F—C₆H₂ — 253 C₂H₅ CH₃OCH₂(C₂H₅)CH H H 2-Cl-4-OCH₃-5-F — 254 C₂H₅ CH₃OCH₂(C₂H₅)CH H H 2-Cl-4,5-(OCH₃)₂ — 255 C₂H₅ CH₃OCH₂(C₂H₅)CH H H 2-CH₃-4-OCH₃-5-F—C₆H₂ — 256 C₂H₅ CH₃OCH₂(C₂H₅)CH H H 2-CH₃-4-OCH₃-C₆H₃ — 257 C₂H₅ CH₃OCH₂(C₂H₅)CH H H 2-CH₃-4-Cl—C₆H₃ — 258 OCH₃ CH₃OCH₂(C₂H₅)CH H H 2,4-Cl₂—C₆H₃ — 259 OCH₃ CH₃OCH₂(C₂H₅)CH H H 2-Cl-4-CH₃O—C₆H₃ — 260 OCH₃ CH₃OCH₂(C₂H₅)CH H H 2,4,6-(CH₃)₃—C₆H₂ — 261 OCH₃ CH₃OCH₂(C₂H₅)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 262 OCH₃ CH₃OCH₂(C₂H₅)CH H H 2-(CH₃)₂N-4-CH₃-pyridin-5-yl — 263 OCH₃ CH₃OCH₂(C₂H₅)CH H H 2,4,6-(OCH₃)₃—C₆H₂ — 264 OCH₃ CH₃OCH₂(C₂H₅)CH H H 2,4-Cl₂-5-F—C₆H₂ — 265 OCH₃ CH₃OCH₂(C₂H₅)CH H H 2-Cl-4-OCH₃-5-F — 266 OCH₃ CH₃OCH₂(C₂H₅)CH H H 2-Cl-4,5-(OCH₃)₂ — 267 OCH₃ CH₃OCH₂(C₂H₅)CH H H 2-CH₃-4-OCH₃-5-F—C₆H₂ — 268 OCH₃ CH₃OCH₂(C₂H₅)CH H H 2-CH₃-4-OCH₃—C₆H₃ — 269 OCH₃ CH₃OCH₂(C₂H₅)CH H H 2-CH₃-4-Cl—C₆H₃ — 270 C₂H₅ (C₂H₅)₂CH H H 2-Cl-4-CF₃—C₆H₃ oil^(i) 271 OCH₃ (C₂H₅)₂CH H H 2-Cl-4-CF₃—C₆H₃ — 272 C₂H₅ C₄H₉(C₂H₅)CH H H 2-Cl-4-CF₃—C₆H₃ — 273 OCH₃ C₄H₉(C₂H₅)CH H H 2-Cl-4-CF₃—C₆H₃ — 274 C₂H₅ (C₂H₅)₂N H H 2-Cl-4-CF₃—C₆H₃ — 275 OCH₃ (C₂H₅)₂N H H 2-Cl-4-CF₃—C₆H₃ — 276 C₂H₅ C₃H₇(CH₃)CH H H 2-Cl-4-CF₃—C₆H₃ — 277 OCH₃ C₃H₇(CH₃)CH H H 2-Cl-4-CF₃—C₆H₃ — 278 C₂H₅ C₂H₅(OCH₃)CH H H 2-Cl-4-CF₃—C₆H₃ — 279 OCH₃ C₂H₅(OCH₃)CH H H 2-Cl-4-CF₃—C₆H₃ — 280 C₂H₅ CH₃OCH₂(CH₃)CH H H 2-Cl-4-CF₃—C₆H₃ — 281 OCH₃ CH₃OCH₂(CH₃)CH H H 2-Cl-4-CF₃—C₆H₃ —

[0465] Key:

[0466] a) Spectral data for Example 1: ¹H NMR (300 MHz, CDCl₃): δ(1H, d, J=4.1 Hz), 7.58 (1H, d, J=2.0 Hz), 7.55 d, J=8.2 Hz), 7.41 (1H, dd, J=8.2, 2.0 Hz), 6.65 d, J=4.1 Hz), 2.79 (2H, q, J=7.7 Hz), 2.78-2.68 (1H, m), 2.03-1.79 (4H, m), 1.25 (3H, t, J=7.7 Hz), 0.83 (6H, t, J=7.3 Hz) . MS (NH₃-CI): m/e 367 (2), 366 (11), 365 (15), 364 (65), 363 (25), 362 (100). Analysis calc'd for C₁₉H₂₁Cl₂N₃: C, 62.99; H, 5.84; N, 11.60; found: C, 62.97; H, 5.74; N, 11.49.

[0467] b) Spectral data for Example 3: ¹H NMR (300 MHz, CDCl₃): δ8.36 (1H, d, J=5.0 Hz), 7.00 (2H, s), 6.50 (1H, d, J=5.0 Hz), 2.77 (2H, q, J=7.7 Hz), 2.76-2.66 (1H, m), 2.36 (3H, s), 2.02 (6H, s), 2.00-1.80 (4H, m), 1.21 (3H, t, J=7.7 Hz), 0.83 (6H, t, J=7.5 Hz) . MS (NH₃-CI): m/e 338 (3), 337 (24), 336 (100). Analysis calc'd for C₂₂H₂₉N₃: C, 78.76; H, 8.71; N, 12.53; found: C, 78.74; H, 8.74; N, 12.41.

[0468] c) Spectral data for Example _(1-6:) ¹H NMR (300 MHz, CDCl₃): 8 8.39 (1H, d, J=4.2 Hz), 7.59 (1H, d, J=8.3 Hz), 7.58 (1H, d, J=2.0 Hz), 7.42 (1H, dd, J=8.3, 2.0 Hz), 6.65 (1H, d, J 4.2 Hz), 2.82-2.72 (1H, m), 2.79 (2H, q, J=7.3 Hz), 2.00-1.77 (4H, m), 1.35-1.10 (4H, m), 1.25 (3H, t, J=7.3 Hz), 0.83 (3H, t, J=7.0 Hz), 0.82 (3H, t, J =7.5 Hz). MS (NH₃-CI): m/e calculated for C₂₁H₂₆Cl₂N₃: 390.1504, found 390.1502; 395 (3), 394 (12), 393 (17), 392 (67), 391 (29), 390 (100).

[0469] d) Spectral data for Example 18: ¹H NMR (300 MHz, CDCl₃): δ8.36 (1H, d, J=4.0 Hz), 7.00 (2H, s), 6.50 (1H, d, J=4.0 Hz), 2.82-2.73 (1H, m), 2.77 (2H, q, J=7.6 Hz), 2.36 (3H, s), 2.02 (3H, s), 2.01 (3H, s), 2.00-1.78 (4H, m), 1.38-1.09 (4H, m), 1.20 (3H, t, J=7.6 Hz), 0.83 (3H, t, J=7.0 Hz), 0.81 (3H, t, J=7.3 Hz). MS (NH3-CI): m/e calc'd for C₂₄H₃₄N₃: 364.2753, found 364.2754; 366 (4), 365 (27), 364 (100).

[0470] e) Spectral data for Example 31: ¹ ¹H NMR (300 MHz, CDCl₃): δ8.38 (1H, d, J=4.0 Hz), 7.58 (1H, d, J=1.8 Hz), 7.56 (1H, d, J=8.4 Hz), 7.42 (1H, dd, J=8.4, 1.8 Hz), 6.65 (1H, d, J=4.0 Hz), 3.27 (4H, q, J=7.3 Hz), 2.80 (2H, q, J=7.3 Hz), 1.26 (3H, t, J=7.3 Hz), 1.00 (6H, t, J =7.3 Hz). MS (NH₃-CI): calculated for C₁₈H₂₁C₁₂N₄ : 363.11-43, found 363.11-46; m/e 367 (6), 366 (₁₋₄), 365 (81), 364 (28) , 363 (100).

[0471] f) Spectral data for Example 51: ¹ ¹H NMR (300 MHz, CDCl₃) : δ8.27 (1H, s), 7.60 (1H, d, J=2.2 Hz), 7.43 (1H, dd, J=8.0, 2.0 Hz), 7.32 (1H, d, J=8.0 Hz), 3.84 (3H, s), 2.80-2.70 (1H, m), 2.08 (3H, s), 1.86-1.70 (4H, m), 0.82 (6H, t, J=7.4 Hz). MS (NH₃-CI) : mle 383 (2), 382 (12), 381 (₁₋₄), 380 (65), 379 (25), 378 (100).

[0472] g) Spectral data for Example 155: ¹H NMR (300 MHz, CDCl₃): δ8.39 (1H, d, J=4.0 Hz), 7.63 (1H, d, J=6.6 Hz), 7.48 (1H, d, J=8.8 Hz), 6.67 (1H, d, J=4.0 Hz), 2.79 (2H, q, J=7.4 Hz), 2.78-2.68 (1H, m), 2.03-1.79 (4H, m), 1.26 (3H, t, J=7.4 Hz), 0.83 (6H, t, J=7.5 Hz). MS (NH₃-CI): m/e 384 (11), 383 (₁₋₆), 382 (79), 381 (20), 380 (100).

[0473] h) Spectral data for Example 198: ¹ ¹H NMR (300 MHz, CDCl₃): δ8.40 (1H, d, J=4.0 Hz), 7.58 (1H, d, J=1.8 Hz), 7.55 (1H, d, J=8.4 Hz), 7.41 (1H, dd, J=8.4, 1.8 Hz), 6.67 (1H, d, J=4.0 Hz), 3.79 (2H, d, J=7.3 Hz), 3.38 (3H, s), 3.37 (1H, m), 2.82 (2H, q, J=7.3 Hz), 1.47 (3H, d, J=7.0 Hz), 1.25 (3H, t, J=7.3 Hz). Mass Spectrum (AP-CI): m/e 364 (100), 366 (65), 368 (12.5). High resolution mass spectrum: for C₁₈H₂OC₁₂N₃O m/e calculated: 364.0984, observed 364.0988.

[0474] i) Spectral data for Example 270: TLC R_(F) 0.19 (5:95 ethyl acetate-hexane). ¹ ¹H NMR (300 MHz, CDCl₃): δ8.42 (1H, d, J =4.4 Hz), 7.84 (1H, br s), 7.76 (1H, d, J=8.1 Hz), 7.69 (1H, d, J=8.1 Hz), 6.68 (1H, d, J=4.4 Hz), 2.79 (2H, q, J=7.7 Hz), 2.78-2.68 (1H, m), 2.02-1.80 (4H, m), 1.25 (3H, t, J=7.7 Hz), 0.84 (6H, t, J=7.5 Hz). MS (NH₃-CI): m/e 399 (7), 398 (33), 397 (25), 396 (100). Analysis calc'd for C₂₀H₂₁ClF₃N₃: C, 60.68; H, 5.36; N, 10.62; found: C, 60.66; H, 5.15; N, 10.48. cl Additional Examples of Compounds Made According to the Above-Described Synthetic Scheme and Examples

[0475] 7-(2,4-dichloro-5-fluorophenyl)-2-ethyl-3-(2-pentyl)-pyrazolo[1,5-a]pyrimidine

[0476] 7-(2,4-dichlorophenyl)-2-ethyl-6-methyl-3-(2-pentyl)-pyrazolo[1,5-a]pyrimidine

[0477] 7-(2-chloro-4-methoxyphenyl)-2-ethyl-3-(2-pentyl)pyrazolo[1,5-a]pyrimidine

[0478] 2-ethyl-3-(2-pentyl)-7-(2,4,6-trimethylphenyl)-pyrazolo[1,5-a]pyrimidine

[0479] 2-ethyl-3-(2-pentyl)-7-(2,4,6-trimethoxyphenyl)-pyrazolo[1,5-a]pyrimidine

[0480] 7-(2,4-dichlorophenyl)-2-ethyl-3-(2-pentyl)pyrazolo[1,5-a]pyrimidine

[0481] 7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyrimidine-3-carboxaldehyde

[0482] 7-(2,4-dichlorophenyl)-2-ethyl-3-(1-hydroxyethyl)-pyrazolo[1,5-a]pyrimidine

[0483] 7-(2,4-dichlorophenyl)-3-(l-ethoxyethyl)-2-ethyl-pyrazolo[1,5-a] pyrimidine

[0484] 7-(2,4-dichlorophenyl)-3-(1-ethoxyethyl)-2-ethylpyrazolo[1,5-a]pyrimidine

[0485] 2-ethyl-7-(2-methyl-4-methoxyphenyl)-3-(3-pentyl)-pyrazolo[1,5-a]pyrimidine

[0486] 2-ethyl-7-(2-methyl-4-methoxyphenyl)-3-(2-pentyl)-pyrazolo[1,5-a]pyrimidine

[0487] 7-(2,4-dimethylphenyl)-2-ethyl-3-(2-pentyl)-pyrazolo[1,5-a]pyrimidine

[0488] 7-(2,4-dichlorophenyl)-2-ethyl-5-methylthio-3-(2-pentyl)-pyrazolo[1,5-a]pyrimidine

[0489] 7-(2,4-dichlorophenyl)-2-ethyl-3-(6-methyl-5-hepten-2-yl)-pyrazolo[1,5-a]pyrimidine

[0490] 7-(2,4-dichlorophenyl)-2-ethyl-3-(1-hydroxy-4-pentyl)-pyrazolo[1,5-a] pyrimidine

[0491] 7-(4-difluoromethoxy-2-methyl)-2-ethyl-3-(3-pentyl)pyrazolo[1,5-a]pyrimidine

[0492] 7-(4-difluoromethoxy-2-methyl)-2-ethyl-3-(2-pentyl)pyrazolo[1,5-a]pyrimidine

[0493] 7-(2-chloro-4-difluoromethoxyphenyl)-2-ethyl-3-(3-pentyl)pyrazolo[1,5-a]pyrimidine

[0494] 7-(2-chloro-4-difluoromethoxyphenyl)-2-ethyl-3-(2-pentyl)pyrazolo[1,5-a]pyrimidine

[0495] 7-(2,4-dimethylphenyl)-2-ethyl-3-(3-pentyl)pyrazolo[1,5-a]pyrimidine

[0496] 4-(7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyrimidinyl)pentanoic acid

[0497] 4-(7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyrimidinyl)-N-methylpentanamide

[0498] 3-(5-(benzoxazol-2-ylthio)-2-pentyl)-7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyrimidine

[0499] 3-(5-(benzoxazolidinethione-3-yl)-2-pentyl)-7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyrimidine

[0500] 7-(2,4-dichlorophenyl)-2-ethyl-3-(1-hydroxy-2-propyl)-pyrazolo[1,5-a]pyrimidine

[0501] 7-(2,4-dichlorophenyl)-3-(1-ethoxy-2-propyl)-2-ethyl-pyrazolo[1,5-a]pyrimidine

[0502] 3-(l-acetoxy-2-propyl)-7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyrimidine

[0503] 3-(l-acetoxy-2-butyl)-7-(2,4-dichlorophenyl)-2-ethylpyrazolo[1,5-a]pyrimidine

[0504] 7-(2,4-dichlorophenyl)-2-ethyl-3-(l-hydroxy-3-butyl)pyrazolo[1,5-a]pyrimidine

[0505] 7-(2,4-dichlorophenyl)-2-ethyl-3-(l-methoxy-3-butyl)pyrazolo[1,5-a]pyrimidine

[0506] 7-(2,4-dichlorophenyl)-2-ethyl-3-(3-heptyl)-pyrazolo[1,5-a]pyrimidine

[0507] 7-(2,4-dichlorophenyl)-2-ethyl-3-(3-heptyl)-6-methyl-pyrazolo[1,5-a]pyrimidine

[0508] 2-ethyl-3-(3-heptyl)-7-(2,4,6-trimethylphenyl)-pyrazolo[1,5-a]pyrimidine

[0509] 7-(2,4-dichlorophenyl)-2-ethyl-3-(3-pentyl)-pyrazolo[1,5-a]pyrimidine

[0510] 7-(2,4-dichlorophenyl)-2-ethyl-3-(3-pentyl)-6-methyl-pyrazolo[1,5-a]pyrimidine

[0511] 2-ethyl-3-(3-pentyl)-7-(2,4,6-trimethylphenyl)-pyrazolo[1,5-a]pyrimidine

[0512] 2-ethyl-3-(3-pentyl)-7-(2,4,6-trimethoxyphenyl)-pyrazolo[1,5-a]pyrimidine

[0513] Although the present invention has been described and exemplified in terms of certain preferred embodiments, other embodiments will be apparent to those skilled in the art. The invention is, therefore, not limited to the particular embodiments described and exemplified, but is capable of modification or variation without departing from the spirit of the invention, the full scope of which is delineated by the appended claims. 

What is claimed is:
 1. A compound of formula I:

or a stereoisomer or pharmaceutically accetable salt thereof, wherein: R¹ is selected from the group consisting of C₁₋₆alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylS(O)_(n), -NR^(1a) R^(1b) wherein R^(1a) and R^(1b) are independently selected from H, C₁₋₄ alkyl, -C(O)C₁₋₄alkyl, -C(O)NR^(1a)R^(1b), —O—C (O) C₁₋₄alkyl, -XR^(1c) wherein R^(1c) is selected from H or -C₁₋₄ alkylaryl; X is selected from 0 or S(O)_(n), wherein R¹ is substituted with 0-6 substituents selected from halogen, C₁₋₄ alkyl, C₁₋₆ alkyloxy, C₁₋₄ haloalkyl, -N^(1a) N^(1b) Xlc NR^(1a)R^(1b), XR^(1c); R is selected from the group consisting of C₁₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl, C₁₋₁₀ alkyloxy, C₁₋₁₀alkyloxyC₁₋₁₀ alkyl, -SO₂-C₁₋₁₀alkyl -SO₂R^(2a) wherein R^(2a) is aryl, -SO₂R^(2b) wherein R^(2b) is heteroaryl, -NR^(2C)R^(2D) wherein R^(2c) and R^(2d) are independently selected from H, C₁₋₈ alkyl, S (O)_(n)C₁₋₄alkyl, C (O)NR^(2c)R^(2d), CO_(2c)C₁₋₄alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkyloxyC₁₋₆ alkyl, -C(O)C₁₋₄alkyl or R^(1c) and R^(2d) may join to form a heterocyclic ring having 0-3 heteroatoms selected from O, N or S, -halogen, -CN, -C(O)L wherein L is selected from NR^(2c)CR^(2d), C₁₋₆ alkyl, H, -OC₁₋₆ alkyl, O(CH₂)_(m)OC₁₋₆alkyl, O(CH₂)_(m)NR^(2c)R^(2d), -OH, aryl, heteroaryl or C(O)OC₁₋₆ alkyl wherein m is 1-3; n is 0, 1 or 2; R² is substituted with 0-3 substituents independently selected from R′, R″, R″′ wherein R′, R″ and R″′ are independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, hydroxyC₁₋₆ alkyl, C₁₋₆ alkyloxyC₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkyloxy, hydroxy; or R² is substituted with 0-3 substitutents independently selected from halogen, -CN, -S(O)_(n)R^(2e) wherein R^(2e) is selected from C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkyloxy C₁₋₄ alkyl, C₃₋₆ cycloalkyl; -COR^(2f) wherein R^(2f) is selected from H, C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkyloxy C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkylc₁₋₄ alkyl; - CO₂R^(2f), -NR^(2g)COR^(2f) wherein R^(2g) is selected from H, C₁₋₆ alkyl, C₃₋₇ c-alkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl; -N(COR^(2f) )₂, -NR^(2g)CONR^(2f)R^(2h) wherein R^(2h) is selected from H, C₁₋₆ alkyl, C₄ haloalkyl, C₁₋₄ alkoxy C₁₋₄ alkyl, C₃₋₆ cycloalkyl and C₃,₆ cycloalkylC₁₋₆ alkyl; -NR^(2g)CO₂R^(2e), 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C₃₋₈ cycloalkyl wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from -O-, -S(O)_(n), -NR^(2g), -NCO₂R^(2e), -NCOR^(2e), and -NSO₂R^(2e); and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from R^(2g), CO₂R^(2e), COR^(2e) and SOR^(2e); or the group R^(2i), R^(2j), R^(2k), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -OR^(2g), -NR^(2g)R^(2h), -C₁₋₆ alkylOR_(2g), and C₃₋₈ cycloalkyl which is substituted with 0-1 R^(2l) and in wich 0-1 carbons of C₄₋₈ cycloalkyl is replaced by -O-, wherein R^(2i) is selected from aryl wherein aryl includes phenyl, naphthyl, indanyl and indenyl, each R^(2i) being substituted with 0-1 OR^(2m) and 0-5 substituents independently selected from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, nitro, -SH, -S(O)_(n)R^(2n), -COR^(2m), -OC(O)R^(2n), -NR^(2g)COR^(2m), -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p), -NR^(2g)CO₂R^(2n), -NR^(2o)R^(2p) and -CONR^(2o)R^(2p); R^(2j) is selected from heteroaryl wherein heteroaryl includes pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-s-oxide, 2,3-dihydro-benzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, nitro, OR^(2m), -SH, -S(O)_(n)R^(2h), -COR^(2m) ₁ OC(O)R^(2h) -NR^(2g)COR^(2m), -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p), -NR^(2g)CO₂R^(2h), -NR^(2o)R^(2p) and -CONR^(2o)R^(2p) and each heteroaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(2g), CO₂R^(2e), COR^(2e) and SO₂R^(2e); R^(2k) is heterocyclyl which is a saturated or partially saturated heteroaryl as defined for R^(2j) each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, nitro, -OR -SH, -S(O)_(n)R^(2h), -COR^(2m), -OC(O)R^(2h), -NR^(2g)COR^(2m), -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p), NR^(2g)CO₂R^(2h), -NR^(2o)R^(2p) and -CONR^(2o)R^(2p) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(2f), CO₂R^(2e), COR^(2e) and SO₂R^(2e); wherein R^(2l) is H, C₁₋₄ alkyl, C₃₋₆ cycloalky-C₁₋₄ alkyl and C₃₋₈ cycloalkyl; R^(2m) is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl, C₁₋₂ alkyloxy C₁₋₂ alkyl, C₁₋₄ haloalkyl, R^(2q)(O)_(n)-C₁₋₄ alkyl and R^(2r)R^(2s)N-C₂₋₄ alkyl; R^(2n), is H, C₁₋₆ alkyl, C₃₋₁₀ cyloalkyl, C₃₋₆ cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkyloxy C₁₋₂ alkyl, and C₁₋₄ haloalkyl; R^(2o) and R^(2p) are independently selected at each occurrence from H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆cycloalkyl C₁₋₆ alkyl and C₁₋₄ haloalkyl; R^(2q) is selected from C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl- C₁₋₆ alkyl, aryl, aryl(C₁₋₄ alkyl), heteroaryl and heleroaryl (C₁₋₄ alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy C₁₋₄ haloalkoxy, and dimethylamino; R^(2r)R^(2s) taken together with the N form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl wherein N₄ in 1-piperiazinyl is substituted with 0-1 substituents selected from the group R^(2t), CO₂R^(2q), COR^(2q) and SO₂R^(2q); R^(2t) is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy -C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl -C₁₋₆ alkyl, aryl, aryl (C₁₋₄ alkyl)-, heteroaryl and heteroaryl (C₁₋₄ alkyl); R³ is selected from an aryl or heteroaryl group attached through an unsaturated carbon atom; aryl is selected from phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkyloxy-C alkyloxy, -OR^(2m), Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, -NO₂, -SH, -S(O)_(n)R^(2m), -COR^(2m), -CO₂R^(2m), -OC(O)R^(2n), -NR^(2g)COR^(2p), -N (COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p), -NR^(2g)CO₂R^(2h), -NR^(2o)R^(2p) and CONR^(2o)R^(2p) and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, -CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl; heteroaryl is selected from the group pyridyl, pyrimidyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzo-furanyl, 2,3-dihydrobenzothienyl, 2,3-dihydro-benzothienyl-S-oxide, 2,3-dihydrobenzothienyl-s-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substitued at 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, F, I, C₁₋₄ haloalkyl, -CN, NR^(2g)R^(2h), nitro, -OR^(2m), -SH, -S (O)_(n)R^(2n), COR^(2m), -CO₂R^(2m), -OC(O)R^(2n), - N (COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p) and each heteroaryl being substituted at any nitrogen atom with 0-1 substituents selected from the group R^(2g), CO₂R^(3a), COR^(3a) and SO₂R^(3a) wherein, R^(3a) is selected from the group C₁₋₆ alkyl, C₁₋₄ cycloalkyl-C₁₋₆ alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₀₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino; R⁴ and R⁵ are independently selected at each occurrence from H, Br, Cl, F, I, -CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, amino, C₁₋₄ alkylamino, (C₁₋₄ alkyl)₂ amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group consisting of C₁₋₇ alkyl, C₃₋₈ cycloalkyl, Br, Cl, F, I, -C(O)H, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkylamino and (C₁₋₄ alkyl)₂ amino and wherein R⁴ and R⁵ non-phenyl groups may be substituted with 0-5 substituents selected from OH, halogen, -C(O)H, -OC₁₋₆-alkyl and C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₇ c-alkyl, C₁₋₆ alkyl(OH)_(n)CO₂R wherein R is H or C₁₋₆ alkyl, C₁₋₆ alkyl(OH)_(n), wherein n is 0-3 or R⁴ and R⁵ may join together to form a C₃₋₆ alkylene chain; with the proviso that the compounds of Formula I with R¹, R², R³ , R⁴ and R⁵ as specifically defined below are excluded: (a) a compound of formula I wherein R¹ is unsubstituted, unbranched (linear) C₁₋₃ alkyl and R² is -C(O)-Ph; (b) a compound of formula I, wherein R⁵ is H or C₁₋₃ alkyl and R³ is pyridyl, pyridyl-N-oxide, thien-3-yl or furan-3-yl or C₁₋₃ alkyl substituted versions thereof and R¹ is carboamoyl or unsubstituted, unbranched C₁₋₃ alkyl, R² is F, Cl, Br, formyl, carboxyl, CN, hydroxymethyl, unsubstituted, unbranched C₁₋₃ alkyl, -C(O)R, -C(O)OR, -CH₂OR, -C(O)O(CH₂)₂OR, -C(O)O(CH₂)₂NHR, or -C(O)O(CH₂)₂NR² wherein R is C_(1═3) alkyl; (c) a compound of formula I, wherein R¹ is unsubstituted, unbranched C₁₋₃ alkyl and R² is halogen, CN or -C(O)R wherein R is H, C₁₋₃ alkyl or C₁₋₄ alkoxy, R³ is Ph substituted with NR^(2g)(O)R^(2m); (d) a compound of formula I, R² is CN, halogen, CO₂R with R equal to C₁₋₃ alkyl, unsubstituted, unbranched C₁₋₃ alkyl, C₁₋₃ haloalkyl or CONH₂ and R⁵ is equal to OR, SR wherein R is C₁₋₃ alkyl, C₁₋₄ haloalkyl or C₃₋₄ halocycloalkyl, and R³ is phenyl or substituted phenyl; (e) a compound of formula I, wherein R¹ is H or C₁₋₃ alkyl; R³ is phenyl, ortho-trifluoromethylphenyl, meta-trifluorophenyl or meta-methoxyphenyl; R¹ is carbamoyl or unsubstituted, unbranched C₁₋₃ alkyl; R² is halogen, formyl, carboxyl, cyano, hydroxymethyl, unsubstituted, unbranched C₁₋₃ alkyl, -C(O)R, -C(O)OR, CH₂OR, -C(O)O(CH₂)₂OR, -C(O)O(CH₂)₂NHR or -C(O)O(CH₂)₂NR² wherein R is C₁₋₃ alkyl; (g) in a compound of formula I, R² is CN, R¹ is methyl, R⁴ and R⁵ are H, R³ is phenyl substituted with imidazo (or 2-methylimidazo) through the imidazo nitrogen atom; (h) in a compound of formula I, R² is CN, R¹ is SCH₃, R³ is para-chlorophenyl, R⁴ is SCH₃ and R⁵ is H; (i) in a compound of formula I, R² is CN, R¹ is SCH₃₁ R³ is pyrid-4-yl, R⁴ is SCH₃, and R⁵ is H; (j) in a compound of formula I, R² is CN, R¹ is SCH₃, R³ is Ph, R⁴ is SCH₃ and R⁵ is H; (k) in a compound of formula I, R² is C(O)NH_(2,) R¹ is SCH₃, R³ is pyrid-3-yl, R⁴ is SCH₃ and R⁵ is H; (l) in a compound of formula I, R² is C(O)NH₂, R¹ is SCH₃, R² is Ph, R⁴ is SCH₃ (or Ph) and R⁵ is H; (m) in a compound of formula I, R² is C(O)OEt, R¹ is SCH₃, R³ is Ph, R⁴ is SCH₃ (or Ph) and R⁵ is H; (n) in a compound of formula I, R¹ is N(C(O)CH₃)₂, R² is CH₂Ph (p-Me, p-Cl), R³ is Ph (p-ClPh) , R⁴ is SCH₃and R⁵ is H; (o) in a compound of formula I, R¹ is N(C(O)CH₃)₂ R²i CH₂Ph(p-OMe), R³ is p-ClPh, R⁴ is SCH₃ and R⁵ is H (p) in a compound of formula I, R² is CN, R¹ is CH₃, R³is Ph, R⁴ is H and R⁵ is H; (q) in a compound of formula I, R² is C(O)NH₂, R¹ is CH₃,R is Ph. R⁴ is CH₃ and R⁵ is H; (s) in a compound of formula I, R² is C(O)NH₂ R¹ is CH₃, R³ is pyrid-4-yl, R⁴ and R⁵ are H; (t) in a compound of formula I, R² is C(O)NH₂, R¹ is CH₃, R³ is m-CF₃Ph, R⁴ and R⁵ are H; (u) in a compound of formula I, R² is CN, R¹ is CH₃, R³ is Ph, R⁴ is CH₃ and R⁵ is H; (v) in a compound of formula I, R² is CN, R¹ is CH₃, R³ is pyrid-4-yl, R⁴ and R⁵ are H; (x) in a compound of formula I, R² is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is CH═CH—CH(OH)CH₂CH(OH)CH₂C(O)O-iPr; (y) in a compound of formula I, R² is CH₃, R¹ is CH₃, R is p-F-Ph, R⁴ is c-propyl and R⁵ is CH═CH—CH(OH)CH₂CH(OH)CH₂C(O)O-nPr; (z) in a compound of formula I, R² is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is CH═CH—CH(OH) CH₂CH(OH) CH₂C (O) OMe; (aa) in a compound of formula I, R² is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is CH═CH—CH (OH) CH₂CH (OH) CH₂C (O) OH; (bb) in a compound of formula I, R² is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is -CH₂OH; (cc) in a compound of formula I, R is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is -C(O)H; (dd) in a compound of formula I, R² is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is —CH═CH—C(O)H; (ee) in a compound of formula I, R² is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is CH═CH—CH(OH)CH₂CH(OH) CH₂C(O)OEt; (ff) in a compound of formula I, R² is CH₃, R¹ is CH₃, R³ is p-F-Ph, R⁴ is c-propyl and R⁵ is CH═CH—CH(OH) CH₂CH(OH) CH₂C (O) ONa⁺; (gg) in a compound of formula I, R² is CN, R¹ is CF₃, R³ is m-Cl-Ph, R⁴ is CH₃ and R⁵ is H; (hh) in a compound of formula I, R² is CN, R¹ is CF₃, R³ is m-CF₃-Ph, R⁴ is CH₃ and R⁵ is H; (ii) in a compound of formula I, R² is CN, R¹ is CF₃, R³ is Ph, R⁴ is CH₃ and R⁵ is H; (nn) in a compound of formula I, R² is -C(O)NH₂, R¹ is Me, R³ is Ph, R⁴ is H and R⁵ is Me; (oo) in a compound of formula I, R² is CN, R¹ is Me, R³ is Ph, R⁴ is H and R⁵ is Me; (pp) in a compound of formula I, R² is CN, R¹ is Me, R³ is o-Cl, m-Cl-Ph, R⁴ is H and R⁵ is H; (qq) in a compound of formula I, R² is C(O)NH₂, R¹ is CH₃, R³ is Ph, R⁴ and R⁵ are H; (rr) in a compound of formula I, R² is C(O)NH₂, R¹ is CH₃, R³ is O-CL, m-Cl-Ph, R⁴ and R⁵ are H; (ss) in a compound of formula I, R² is C(O)OMe, R¹ is -SCH₂-Ph, R³ is Ph, R⁴ is Me and R⁵ is H; (tt) in a compound of formula I, R² is C(O)OMe, R¹ is -SCH₂-Ph, R³ is Ph, R⁴ is H and R⁵ is H; (uu) in a compound of formula I, R² is C(O)Ph, R¹ is Me, R³ is pyrid-4-yl, R⁴ and R⁵ are H; (vv) in a compound of formula I, R² is C(O)Ph, R¹ is Me, R³ is m-CF₃-Ph, R⁴ and R⁵ are H; (ww) in a compound of formula I, R² is C(O)Ph, R¹ is Me, R³ is pyrid-3-yl, R⁴ and R⁵ are H; (xx) in a compound of formula I, R² is CN, R is SCH₃, R³ is Ph, R⁴ is Ph and R⁵ is H; (yy) in a compound of formula I, R² is CN, R¹ is SCH₃, R³ is Ph, R⁴ is Ph and R⁵ is H; (zz) in a compound of formula I, R² is Cl, R¹ is Et, R³ is pyrid-3-yl, R⁴ and R⁵ are H; (aaa) in a compound of formula I, R is CO₂H, R¹ is Et, R³ is pyrid-3-yl, R⁴ and R⁵ are H; (bbb) in a compound of formula I, R² is CO₂H, R¹ is CH₃, R³ is pyrid-3-yl, R⁴ and R⁵ are H and H Cl salt ; (ccc) in a compound of formula I, R² is C(O)OEt, R¹ is CH₃, R³ is pyrid-3-yl, R⁴ and R⁵ are H; (ddd) in a compound of formula I, R² is CN, R¹ is CH₃, R³ is pyrid-3-yl, R⁴ is H and R⁵ is CH₃; (eee) in a compound of formula I, R² is CN, R¹ is CH₃, R³ is pyrid-3-yl, R⁴ and R⁵ are H; (fff) in a compound of formula I, R² is C(O)OEt, R¹ is Et, R³ is pyrid-3-yl, R⁴ and R⁵ are H; (ggg) in a compound of formula I, R² is CN, R¹ is Et, R³ is pyrid-3-yl, R⁴ and R⁵ are H; (hhh) in a compound of formula I, R² is CN, R¹ is CH₃, R³ is m-CF₃Ph, R⁴ and R⁵ are H; (iii) in a compound of formula I, R² is CN, R¹ is CH₂CN, R³ is m-CF₃-Ph, R⁴ and R⁵ are H; (jjj) in a compound of formula I, R² is C(O)OMe, R¹ is Me, R³ is m-CF₃-Ph, R⁴ and R⁵ are H; (kkk) in a compound of formula I, R² is CN, R¹ is Et, R³ is m-OMe-Ph, R⁴ and R⁵ are H; (lll) in a compound of formula I, R² is C(O)OEt, R¹ is Et, R³ is Ph, R⁴and R⁵ are H; (mmm) in a compound of formula I, R² is C(O)OEt, R¹ is Et, R³ is m-CF₂-Ph, R⁴ and R⁵ are H; (nnn) in a compound of formula I, R² is CN, R¹ is Et, R³ is m-CF -Ph, R⁴ is H and R⁵ is CH₃; (ooo) in a compound of formula I, R² is CN, R¹ is Et, R³ is m-CF₃, R⁴ and R⁵ are H: (ppp) in a compound of formula I, R² is CN, R¹ is C(O)NH₂, R³ is m-CF -Ph, R⁴ and R⁵ are H; (qqq) in a compound of formula I, R is CN, R¹ is Et, R³ is Ph, R⁴ and R⁵ are H;
 2. A compound of formula I:

or a stereoisomer or pharmaceutically acceptable salt thereof, wherein: R¹ is selected from the group consisting of C₁₋₆ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₆ cycloalkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylS(O)_(n), -NR^(1a)R^(1b) wherein R^(1a) and R^(1b) are independently selected from H, C₁₋₄ alkyl, -C(O)C₁₋₄alkyl, -C(O)NR^(1a)R^(1b), -O-C (O) C₁₋₄alkyl, -XR^(1c) wherein R^(1c) is selected from H or -C₁₋₄ alkylaryl; X is selected from 0 or S(O)_(n), wherein R¹ is substituted with 0-6 substituents selected from halogen, C₁₋₄ alkyl, C₁₋₆ alkyloxy, C₁₋₄ haloalkyl, -NR^(1a)R^(1b), XR^(1c); R² is selected from the group consisting of C.lo alkyl excluding unsubstituted, unbranched C₁₋₃alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl, c, -io alkyloxy, Cl_1 alkyloxyC₁l₀ alkyl, C₁₋₄ alkoxy C₁₋₄ alkyl, -SO₂-cl loalkyl -S0₂R²a wherein R is aryl, -SO₂R^(2b) wherein R^(2b) is heteroaryl, -NR²CR²D wherein R²and R^(2d) are independently selected from H, C₁₋₈ alkyl, S (O) nCl₄ alkyl, C (O) NR R^(2d) , Co Cl₄alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkyloxyCl₆ alkyl, -C(O)Cl₄alkyl or R^(2c) and R^(2d) may join to form a heterocyclic ring having 0-3 heteroatoms selected from O, N or S, n is 0, 1 or 2; R² is substituted with 0-3 substituents independently selected from R¹ , R² , RH, wherein R¹ , RH and RH are independently selected from C₁₋₆ alkyl, C₃₋₇ cycloalkyl, hydroxyc ₁₋₆ alkyl, C₁₋₆ alkyloxyC₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkyloxy, hydroxy, or R² is substituted with 0-3 substituents independently selected from: -CN, -S(O)_(n)R^(2e) wherein R^(2e) is selected from C₁₋₄alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkyloxy Cl₄alkyl, C₃₋₆ cycloalkyl; -COR wherein R^(2f) is selected from H, C₁₋₄ alkyl, Cl₄ haloalkyl, C₁₋₄ alkyloxy C₁₋₄ alkyl, C₃₋₆ cycloalkyl, and C₃₋₆ cycloalkylC₁₋₄ alkyl; -CO₂R^(2f), -NR^(2g)COR^(2f) wherein R^(2g) is selected from H, C₁₋₆ alkyl, C₃₋₇c-alkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl; -N(COR^(2f))₂, -NR^(2g)CONR^(2f)R^(2 h), wherein R^(2h) is selected from H, C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy C₁₋₄ alkyl, C₃₋₆ cycloalkyl and C₃₋₆ cycloalkylCl₁₋₆ alkyl; -NR²CO₂R -CONR² R 1-morpholinyl, 1-piperidinyl, 1-piperazinyl, and C₃₋₈ cycloalkyl wherein 0-1 carbon atoms in the C₄₋₈ cycloalkyl is replaced by a group selected from -O-, -S (O)_(n)-, -NR^(2g)-, -NCO₂R^(2e), -NCOR^(2e), and -NSO₂R^(2e); and wherein N₄ in 1-piperazinyl is substituted with 0-1 substituents selected from R^(2g), CO₂R^(2e) COR^(2e) and SO₂R^(2e); or the group R^(2j), R^(2k), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -OR^(2g), -NR^(2g)R^(2h), -C₁₋₆ alkylOR^(2g), and C₃₋₈ cycloalkyl which is substituted with 0-1 R^(2l) and in wich 0-1 carbons of C₄₋₈ cycloalkyl is replaced by -O-, wherein R^(2j) is selected from heteroaryl wherein heteroaryl includes pyridyl, pyrimidinyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, pyrazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzofuranyl, 2,3-dihydrobenzothienyl, 2,3-dihydrobenzothienyl-s-oxide, 2,3-dihydro-benzothienyl-S-dioxide, indolinyl, benzoxazolin-2-onyl, benzodioxolanyl and benzodioxane, each heteroaryl being substituted on 0-4 carbon atoms with a substituent independently selected from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, nitro, OR^(2m), -SH, -S (O)_(n)R^(2h), -COR^(2m), OC(O)R^(2h), -NR^(2g)COR^(2m), -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p), -NR^(2g)CO₂R^(2h), -NR^(2o)R^(2p) and -CONR^(2o)R^(2p) and each hertoaryl being substituted on any nitrogen atom with 0-1 substituents selected from the group R² CO ₂R^(2e) COR^(2e) and SO₂R²e; R^(2k) is heterocyclyl which is a saturated or partially saturated heteroaryl as defined for R^(2g) each heterocyclyl being substituted on 0-4 carbon atoms with a substituent independently selected from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, nitro, -OR^(2m) ₁, -SH, -S (O)_(n)R^(2h), -COR^(2m), -OC(O)R^(2h), -NR^(2g)COR^(2m), -N(COR)₂ -NR^(2g)CONR^(2o)R^(2p) NR^(2g)COR^(2h) -NR^(2o)OR^(2p) and -CONR^(2o)R^(2p) and each heterocyclyl being substituted on any nitrogen atom with 0-1 substituents selected from the group R^(2f), CO₂R^(2e), COR^(2e) and SO₂R^(2e); wherein R^(2l) is H, C₁₋₄ alkyl, C₃₋₆ cycloalky-C₁₋₄ alkyl and C₃₋₈ cycloalkyl; R^(2m) is H, C₁₋₆ alkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl, C₁₋₂ alkyloxy C₁₋₂ alkyl, C₁₋₄ haloalkyl, R^(2q), S (O)_(n)C₁₋₄ alkyl and R^(2r)R^(2s)N-C₂₋₄ alkyl; R^(2n) is H, C₁₋₆ alkyl, C₃₋₁₀ cyloalkyl, C₃₋₆cycloalkyl-C₁₋₆ alkyl, C₁₋₂ alkyloxy C₁₋₂ alkyl, and C₁₋₄ haloalkyl; R^(2o) and R^(2p) are independently selected at each occurrence from H, C₁₋₆ alkyl, C₃₋₁₀ cycloalkyl, C₃₋₆cycloalkyl C₁₋₆ alkyl and C₁₋₄ haloalkyl; R^(2q) is selected from C₁₋₆ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy-C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl- C₁₋₆ alkyl, aryl, arylC(C₁₋₄ alkyl), heteroaryl and heleroaryl (C₁₋₄ alkyl)- and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy C₁₋₄ haloalkoxy, and dimethylamino; R^(2r)R^(2s) taken together with the N form 1-pyrrolidinyl, 1-morpholinyl, 1-piperidinyl or 1-piperazinyl wherein N₄ in 1-piperiazinyl is substituted with 0-1 substituents selected from the group R^(2t), CO₂R^(2q), COR^(2q) and SO₂R^(2q), R^(2t) is selected from H, C₁₋₄ alkyl, C₁₋₄ haloalkyl, C₁₋₄ alkoxy -C₁₋₄ alkyl, C₃₋₆ cycloalkyl, C₃₋₆ cycloalkyl - C₁₋₆ alkyl, aryl, aryl (C₁₋₄ alkyl)-, heteroaryl and heteroaryl (C₁₋₄ alkyl); R³ is selected from an aryl or heteroaryl group attached through an unsaturated carbon atom; aryl is selected from phenyl, naphthyl, indanyl and indenyl, each aryl being substituted with 0-5 substituents independently selected at each occurrence from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkyloxy-C₁₋₄ alkyloxy, -OR^(2m), Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, -NO₂, -SH, -S(O)_(n)R^(2n), -COR^(2m), -CO₂R^(2m)-OC(O)R^(2n), -NR_(2g)COR^(2m), -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p), -NR^(2g)CO₂R^(2h), NR^(2o)R^(2p) and CONR^(2o)R^(2p) and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, -CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl; heteroaryl is selected from the group pyridyl, pyrimidyl, triazinyl, furanyl, quinolinyl, isoquinolinyl, thienyl, imidazolyl, thiazolyl, indolyl, pyrrolyl, oxazolyl, benzofuranyl, benzothienyl, benzothiazolyl, benzoxazolyl, isoxazolyl, triazolyl, tetrazolyl, indazolyl, 2,3-dihydrobenzo-furanyl, 2,3-dihydrobenzothienyl, 2,3-dihydro-benzothienyl-S-oxide, 2,3-dihydrobenzothienyl-s-dioxide, indolinyl, benzoxazolin-2-on-yl, benzodioxolanyl and benzodioxane, each heteroaryl being substitued at 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, F, I, C₁₋₄ haloalkyl, -CN, NR^(2g)R^(2h), nitro, -OR^(2m) -SH -S(O)_(n)R^(2n), COR^(2m), -CO₂R^(2m), -OC(O)R^(2n), -NR^(2g)COR^(2m), -N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p) and each heteroaryl being substituted at any nitrogen atom with 0-1 substituents selected from the group R^(2g), CO₂R^(3a), COR^(3a) and SO₂R^(3a) wherein, R^(3a) is selected from the group C₁₋₆ alkyl, C₁₋₄ cycloalkyl-C₁₋₆ alkyl and benzyl, each benzyl being substituted on the aryl moiety with 0-1 substituents selected from the group C₁₋₄ alkyl, Br, Cl, F, I, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, and dimethylamino; R⁴ and R⁵ are independently selected at each occurrence from H, Br, Cl, F, I, -CN, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₈ cycloalkyl, C₁₋₆ alkyloxy, C₁₋₆ alkylthio, C₁₋₆ alkylsulfinyl, C₁₋₆ alkylsulfonyl, amino, C₁₋₄ alkylamino, (C₁₋₄ alkyl)₂ amino and phenyl, each phenyl is substituted with 0-3 groups selected from the group consisting of C₁₋₇, alkyl, C₃₋₈ cycloalkyl, Br, Cl, F, I, -C(O)H, C₁₋₄ haloalkyl, nitro, C₁₋₄ alkoxy, C₁₋₄ haloalkoxy, C₁₋₄ alkylthio, C₁₋₄ alkylsulfinyl, C₁₋₄ alkylsulfonyl, C₁₋₆ alkylamino and (C₁₋₄ alkyl)₂ amino and wherein R⁴ and R⁵ non-phenyl groups may be substituted with 0-5 substituents selected from OH, halogen, -C(O)H, -OC₁₋₆-alkyl and C₁₋₆ haloalkyl, C₁₋₆ alkyl, C₃₋₇ c-alkyl, C₁₋₆ alkyl(OH)_(n)CO_(n)R wherein R is H or C₁₋₆ alkyl, C₁₋₆ alkyl(OH)_(n), wherein n is 0-3 or R⁴ and R⁵ may join together to form a C₃₋₆ alkylene chain.
 3. The compound according to claim 1 or 2 wherein R¹ is selected from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, C₁₋₆ alkoxy, C₁₋₆ alkylthio, -XR^(2c) wherein R¹ is substituted with 0-6 substituents selected from halogen, C₁₋₄ alkyl or C₁₋₄ haloalkyl; R² is selected from substituted-C₁₋₁₀ alkyl, branched C₃₋₁₀ alkyl, C₂₋₁₀ alkenyl, C₂₋₁₀ alkynyl, C₃₋₈ cycloalkyl, C₃₋₆ cycloalkyl C₁₋₆ alkyl, -NR^(2c)R^(2d) wherein, in the case of substituted-C₁₋₁₀ alkyl, 1-3 substitutents are independently selected from the group R^(2i), R^(2j), R^(2k), C₁₋₆ alkyl, C₂₋₈ alkenyl, C₂₋₈alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -OR^(2g), -NR^(2g)R^(2h), -C₁₋₆ alkylOR^(2g), and C₃₋₈ cycloalkyl which is substituted with 0-1 R^(2l) and in wich 0-1 carbons of C₄₋₈ cycloalkyl is replacedby -O- and wherein the R² groups, other than substituted-C₁₋₁₀ alkyl, are substituted with 0-3 substituents independently selected from the group R^(2i), R^(2j), R^(2k), C₁₋₆alkyl, C₂₋₈ alkenyl, C₂₋₈ alkynyl, Br, Cl, F, I, C₁₋₄ haloalkyl, -OR^(2g) -NR^(2g)R^(2h), -C₁₋₆ alkylOR^(2g) and C₃₋₈ cycloalkyl which is substituted with 0-1 R^(2l)and in wich 0-1 carbons of C₄₋₈ cycloalkyl is replaced by -O-.
 4. The compound according to claims 1 or 2 or 3 wherein R³ is selected from an aryl group selected from phenyl or substituted versions thereof or a heteroaryl group selected from pyridyl or substituted versions thereof.
 5. The compound according to claims 1, 2, 3 or 4 wherein R² is selected from C₁ alkyl of the formula -CR′R″R″′ wherein R′, R″ and R″′ are independently selected from H, C₁₋₆ alkyl, C₃₋₇ cycloalkyl, hydroxyC₁₋₆ alkyl, C₁₋₆ alkyloxyC₁₋₆ alkyl, C₂₋₆ alkenyl, C₁₋₆ alkyloxy, hydroxy, with the proviso that each of R′, R″ and R″′ cannot be H; or R² is selected from NR^(2c)R^(2d) wherein R⁴ and R⁵ are independently selected from H or C₁₋₆ alkyl.
 6. The compound according to claims 1-5 wherein R³ is selected from an aryl or heteroaryl group attached through an unsaturated carbon atom wherein, aryl is phenyl, each phenyl being substituted with 0-5 substituents independently selected at each occurrence from C₁₋₆ alkyl, C₃₋₆ cycloalkyl, methylenedioxy, C₁₋₄ alkyloxy-Cl₄ alkyloxy, -OR , Br, Cl, F, I, C₁₋₄ haloalkyl, -CN, -NO₂, -SH, -S(O)₂R^(2n), -COR^(2m), -CO₂R , -OC (O) R^(2m), NR^(2g)OR^(2m)-N(COR^(2m))₂, -NR^(2g)CONR^(2o)R^(2p), NR^(2g)CO₂R^(2h), -NR^(2o)R^(2p) and CONR^(2o)R^(2p) and up to 1 phenyl, each phenyl substituent being substituted with 0-4 substituents selected from the group C₁₋₃ alkyl, C₁₋₃ alkoxy, Br, Cl, F, I, -CN, dimethylamino, CF₃, C₂F₅, OCF₃, SO₂Me and acetyl and wherein, heteroaryl is selected at each occurrence from pyridyl, each pyridyl being substitued at 0-4 carbon atoms with a substituent independently selected at each occurrence from the group C₁₋₆ alkyl, C₃₋₆ cycloalkyl, Br, F, I, C₁₋₄ haloalkyl, -CN, nitro, -OR^(2m) -SH, -S(O)_(n)R^(2n), COR^(2m), -CO₂R^(2m), -OC(O)R , -NR^(2g)COR^(2m), -N(COR^(2m))_(2,) -NR²CONR²R² and each pyridyl being substituted at any nitrogen atom with 0-1 substituents selected from the group R^(2g), C₂R^(3a), COR¹ and SO₂R^(3a).
 7. A compound of formula (I)

or a pharmaceutically acceptable salt, stereoisomer or prodrug thereof, wherein R¹ is selected from C₁₋₆ alkyl, C₁₋₆ alkyloxy, -SH or OH; R² is selected from C₁₋₄ alkyl which is unsubstituted or substituted with 1-4 substitutents selected from C₁₋₆ alkyl, C₃₋₈ cycloalkyl, C₁₋₆ alkylOR^(2g), C₂₋₆ alkenyl or OR wherein R^(2g) is H or C₁₋₆ alkyl; R³ is selected from an aryl or heteroaryl group bonded through an unsaturated carbon atom that is unsubstituted or substituted with 1-4 substituents selected from Cl, F, I, Br, -OH, CF₃, S(O)_(n)C₁₋₆ alkyl, -OC₁₋₆ alkyl, C₁₋₆ alkyl or NR^(2g)R^(2h) wherein R^(2g) and R^(2h) are independently selected from H or C₁₋₆ alkyl; R⁴ and R⁵ are independently selected from H, C₁₋₆ alkyl or C₁₋₆ alkyloxy, with the proviso that when R¹ and R² are unsubstituted, unbranched C₁₋₃ alkyl, R³ may not be

wherein R¹ is H or C₁₋₃ alkyl and RN is H or o-trifluoromethyl, m-trifluoromethyl or m-methoxy.
 8. The compound according to claims 1-7 wherein R³ is substituted with 2-4 substituents.
 9. A compound of the formula:

or a pharmaceutically acceptable salt or isomer thereof wherein R¹ -R⁵ and other variables are as defined in claims 1-8.
 10. Use of a compound according to claims 1-9 in therapy.
 11. Use of a compound according to claims 1-9 to antagonize a CRF-1 receptor in mammals including humans wherein binding to the receptor causes and ultimately results in the treatment of affective disorder, anxiety, depression, headache, irritable bowel syndrome, post-traumatic stress disorder, supranuclear palsy, immune suppression, Alzheimer's disease, gastrointestinal diseases, anorexia nervosa or other feeding disorder, drug addiction, drug or alcohol withdrawal symptoms, inflammatory diseases, cardiovascular or heart-related diseases, fertility problems, human immunodeficiency virus infections, hemorrhagic stress, obesity, infertility, head and spinal cord traumas, epilepsy, stroke, ulcers, amyotrophic lateral sclerosis, hypoglycemia or a disorder the treatment of which can be effected or facilitated by antagonizing CRF, including but not limited to disorders induced or facilitated by CRF, in mammals comprising administering to the mammal a therapeutically effective amount of a compound of according to claims 1-9.
 12. A pharmaceutical composition comprising a compound according to claims 1-9 and a pharmaceutically acceptable carrier with the proviso that, in a compound of formula I according to claim 1, proviso (d) compounds are not excluded. 